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Approval Package for:

APPLICATION NUMBER:

209445Orig1s002

Trade Name: FETROJA for injection, 1 gram per vial

Generic or Proper cefiderocol Name:

Sponsor: Shionogi, Inc.

Approval Date: September 25, 2020

Indication: This Prior Approval supplemental new drug application provides for the use of FETROJA in patients 18 years of age and older for the treatment of Hospital-acquired Bacterial Pneumonia and Ventilator-associated Bacterial Pneumonia (HABP/VABP) caused by the following susceptible Gram-negative microorganisms: Acinetobacter baumannii complex, Escherichia coli, Enterobacter cloacae complex, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Serratia marcescens. CENTER FOR DRUG EVALUATION AND RESEARCH

209445Orig1s002

CONTENTS

Reviews / Information Included in this NDA Review.

Approval Letter X Other Action Letters Labeling X REMS Officer/Employee List Multidiscipline Review(s) X  Summary Review  Office Director  Cross Discipline Team Leader  Clinical  Non-Clinical  Statistical  Clinical Pharmacology Product Quality Review(s) Clinical Microbiology / Virology Review(s) Other Reviews Risk Assessment and Risk Mitigation Review(s) Proprietary Name Review(s) Administrative/Correspondence Document(s)

CENTER FOR DRUG EVALUATION AND RESEARCH

APPLICATION NUMBER:

209445Orig1s002

APPROVAL LETTER

NDA 209445/S-002 SUPPLEMENT APPROVAL

Shionogi, Inc. Attention: Priyanka Kamath, MS Senior Manager, US Regulatory Affairs 300 Campus Drive Florham Park, NJ 07932

Dear Ms. Kamath:

Please refer to your supplemental new drug application (sNDA) dated and received March 27, 2020, and your amendments, submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act (FDCA), for FETROJA (cefiderocol) for injection, 1 gram per vial.

This Prior Approval supplemental new drug application provides for the use of FETROJA in patients 18 years of age and older for the treatment of Hospital-acquired Bacterial Pneumonia and Ventilator-associated Bacterial Pneumonia (HABP/VABP) caused by the following susceptible Gram-negative microorganisms: Acinetobacter baumannii complex, Escherichia coli, Enterobacter cloacae complex, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Serratia marcescens.

APPROVAL & LABELING

We have completed our review of this application, as amended. It is approved, effective on the date of this letter, for use as recommended in the enclosed agreed-upon labeling.

WAIVER OF ½ PAGE LENGTH REQUIREMENT FOR HIGHLIGHTS

We are waiving the requirements of 21 CFR 201.57(d)(8) regarding the length of Highlights of Prescribing Information. This waiver applies to all future supplements containing revised labeling unless we notify you otherwise.

CONTENT OF LABELING

As soon as possible, but no later than 14 days from the date of this letter, submit the content of labeling [21 CFR 314.50(l)] in structured product labeling (SPL) format using the FDA automated drug registration and listing system (eLIST), as described at

Reference ID: 4676517 NDA 209445/S-002 Page 2

FDA.gov.1 Content of labeling must be identical to the enclosed labeling (text for the Prescribing Information), with the addition of any labeling changes in pending “Changes Being Effected” (CBE) supplements, as well as annual reportable changes not included in the enclosed labeling.

Information on submitting SPL files using eList may be found in the guidance for industry SPL Standard for Content of Labeling Technical Qs and As.2 The SPL will be accessible from publicly available labeling repositories.

Also within 14 days, amend all pending supplemental applications that include labeling changes for this NDA, including CBE supplements for which FDA has not yet issued an action letter, with the content of labeling [21 CFR 314.50(l)(1)(i)] in Microsoft Word format, that includes the changes approved in this supplemental application, as well as annual reportable changes. To facilitate review of your submission(s), provide a highlighted or marked-up copy that shows all changes, as well as a clean Microsoft Word version. The marked-up copy should provide appropriate annotations, including supplement number(s) and annual report date(s).

REQUIRED PEDIATRIC ASSESSMENTS

Under the Pediatric Research Equity Act (PREA) (21 U.S.C. 355c), all applications for new active ingredients (which includes new salts and new fixed combinations), new indications, new dosage forms, new dosing regimens, or new routes of administration are required to contain an assessment of the safety and effectiveness of the product for the claimed indication in pediatric patients unless this requirement is waived, deferred, or inapplicable.

We are deferring submission of your pediatric studies from birth to less than 18 years of age because this product is ready for approval for use in adults and the pediatric studies have not been completed.

Your deferred pediatric studies required by section 505B(a) of the FDCA are required postmarketing studies. The status of these postmarketing studies must be reported annually according to 21 CFR 314.81 and section 505B(a)(4)(C) of the FDCA. These required studies are listed below:

3940-1 Conduct an open-label, randomized, multicenter, active-controlled trial to evaluate the pharmacokinetics, safety and tolerability of FETROJA (cefiderocol) in children from 3 months to less than 18 years of age with complicated Urinary Tract Infections (cUTI) and HABP/VABP.

1 http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm 2 We update guidances periodically. For the most recent version of a guidance, check the FDA Guidance Documents Database https://www.fda.gov/RegulatoryInformation/Guidances/default.htm.

U.S. Food and Drug Administration Silver Spring, MD 20993 www.fda.gov

Reference ID: 4676517 NDA 209445/S-002 Page 3

The dose for this study for children 3 months to less than 18 years of age will be determined by the data from a single-dose, non-comparative study assessing the pharmacokinetics of FETROJA (cefiderocol) in pediatric patients from 3 months to less than 12 years of age with suspected or confirmed Gram-negative infections.

The timetable you submitted on September 22, 2020, states that you will conduct this trial according to the following schedule:

Final Protocol Submission: 01/2021 Study Completion: 12/2023 Final Report Submission: 04/2024

3940-2 Conduct an open-label, single arm, non-comparative study to evaluate the pharmacokinetics, safety and tolerability of multiple doses of FETROJA (cefiderocol) in children from birth to less than 3 months of age with suspected or confirmed Gram-negative infections. The dose for this study will be determined by the data from a single-dose, non-comparative study assessing the pharmacokinetics of FETROJA (cefiderocol) in pediatric patients from birth to less than 3 months of age with suspected or confirmed Gram-negative infections.

The timetable you submitted on September 22, 2020, states that you will conduct this trial according to the following schedule:

Final Protocol Submission: 06/2022 Study Completion: 08/2024 Final Report Submission: 01/2025

FDA considers the term final to mean that the applicant has submitted a protocol, the FDA review team has sent comments to the applicant, and the protocol has been revised as needed to meet the goal of the study or clinical trial.3

Submit the protocol(s) to your IND 116787, with a cross-reference letter to this NDA. Reports of these required pediatric postmarketing studies must be submitted as a new drug application (NDA) or as a supplement to your approved NDA with the proposed labeling changes you believe are warranted based on the data derived from these studies. When submitting the reports, please clearly mark your submission "SUBMISSION OF REQUIRED PEDIATRIC ASSESSMENTS" in large font, bolded type at the beginning of the cover letter of the submission.

3 See the guidance for Industry Postmarketing Studies and Clinical Trials—Implementation of Section 505(o)(3) of the Federal Food, Drug, and Cosmetic Act (October 2019). https://www.fda.gov/RegulatoryInformation/Guidances/default.htm. U.S. Food and Drug Administration Silver Spring, MD 20993 www.fda.gov

Reference ID: 4676517 NDA 209445/S-002 Page 4

These PMRs replace PMR 3744-1 and PMR 3744-2, listed in the November 14, 2019, approval letter. We remind you that there are other postmarketing requirements listed in the November 14, 2019, approval letter that are still open.

REPORTING REQUIREMENTS

We remind you that you must comply with reporting requirements for an approved NDA (21 CFR 314.80 and 314.81).

If you have any questions, call J. Christopher Davi, MS, Senior Regulatory Project Manager, at (301) 796-0702.

Sincerely,

{See appended electronic signature page}

Sumathi Nambiar, MD, MPH Director Division of Anti-Infectives Office of Infectious Diseases Center for Drug Evaluation and Research

ENCLOSURE:  Content of Labeling o Prescribing Information

U.S. Food and Drug Administration Silver Spring, MD 20993 www.fda.gov

Reference ID: 4676517 Signature Page 1 of 1 ------This is a representation of an electronic record that was signed electronically. Following this are manifestations of any and all electronic signatures for this electronic record. ------/s/ ------

SUMATHI NAMBIAR 09/25/2020 05:55:24 PM

( Reference ID: 4676517

CENTER FOR DRUG EVALUATION AND RESEARCH

APPLICATION NUMBER:

209445Orig1s002

LABELING HIGHLIGHTS OF PRESCRIBING INFORMATION ------CONTRAINDICATIONS------These highlights do not include all the information needed to use FETROJA is contraindicated in patients with a known history of severe FETROJA® safely and effectively. See full prescribing information for hypersensitivity to cefiderocol and other beta-lactam antibacterial drugs or FETROJA. other components of FETROJA. (4)

FETROJA (cefiderocol) for injection, for intravenous use ------WARNINGS AND PRECAUTIONS------Initial U.S. Approval: 2019 • Increase in All-Cause Mortality in Patients with Carbapenem-Resistant Gram-Negative Bacterial Infections: An increase in all-cause mortality was ------RECENT MAJOR CHANGES------observed in FETROJA-treated patients compared to those treated with best Indications and Usage (1) 9/2020 available therapy (BAT). Closely monitor the clinical response to therapy Dosage and Administration (2) 9/2020 in patients with cUTI and HABP/VABP. (5.1) Warnings and Precautions (5) 9/2020 • Hypersensitivity Reactions: Serious and occasionally fatal hypersensitivity (anaphylactic) reactions have been reported in patients receiving beta------INDICATIONS AND USAGE------lactam antibacterial drugs. Hypersensitivity was observed with FETROJA. FETROJA is a cephalosporin antibacterial indicated in patients 18 years of Cross-hypersensitivity may occur in patients with a history of penicillin age or older for the treatment of the following infections caused by susceptible allergy. If an allergic reaction occurs, discontinue FETROJA. (5.2) Gram-negative microorganisms: • Clostridioides difficile-Associated Diarrhea (CDAD): CDAD has been • Complicated Urinary Tract Infections (cUTI), including Pyelonephritis reported with nearly all systemic antibacterial agents, including FETROJA. (1.1) Evaluate if diarrhea occurs. (5.3) • Hospital-acquired Bacterial Pneumonia and Ventilator-associated • Seizures and Other Central Nervous System (CNS) Adverse Reactions: Bacterial Pneumonia (HABP/VABP) (1.2) CNS adverse reactions such as seizures have been reported with FETROJA. If focal tremors, myoclonus, or seizures occur, evaluate To reduce the development of drug-resistant bacteria and maintain the patients to determine whether FETROJA should be discontinued. (5.4) effectiveness of FETROJA and other antibacterial drugs, FETROJA should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria. (1.3) ------ADVERSE REACTIONS------• cUTI: The most frequently occurring adverse reactions in greater than or ------DOSAGE AND ADMINISTRATION------equal to 2% of cUTI patients treated with FETROJA were diarrhea, • Administer 2 grams of FETROJA for injection every 8 hours by infusion site reactions, constipation, rash, candidiasis, cough, elevations intravenous (IV) infusion over 3 hours in patients with creatinine clearance in liver tests, headache, hypokalemia, nausea, and vomiting. (6.1) (CLcr) 60 to 119 mL/min. (2 1) • HABP/VABP: The most frequently occurring adverse reactions in • Dose adjustments are required for patients with CLcr less than 60 mL/min, greater than or equal to 4% of HABP/VABP patients treated with (including patients receiving intermittent hemodialysis (HD) or continuous FETROJA were elevations in liver tests, hypokalemia, diarrhea, renal replacement therapy (CRRT)), and for patients with CLcr hypomagnesemia, and atrial fibrillation. (6.1) 120 mL/min or greater. (2.2) • See full prescribing information for instructions on preparation of To report SUSPECTED ADVERSE REACTIONS, contact Shionogi Inc. FETROJA doses. (2.3) at 1-800-849-9707 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. • See full prescribing information for drug compatibilities. (2.4) ------DRUG INTERACTIONS------Use alternate testing methods to confirm positive results of dipstick tests ------DOSAGE FORMS AND STRENGTHS------(urine protein, ketones, or occult blood). (7.1) For injection: 1 gram of cefiderocol as a lyophilized powder for reconstitution in single-dose vials. (3) See 17 for PATIENT COUNSELING INFORMATION.

Revised: 9/2020

FULL PRESCRIBING INFORMATION: CONTENTS* 7 DRUG INTERACTIONS 1 INDICATIONS AND USAGE 7.1 Drug/Laboratory Test Interactions 1.1 Complicated Urinary Tract Infections (cUTIs), Including 8 USE IN SPECIFIC POPULATIONS Pyelonephritis 8.1 Pregnancy 1.2 Hospital-acquired Bacterial Pneumonia and Ventilator- 8.2 Lactation associated Bacterial Pneumonia (HABP/VABP) 8.4 Pediatric Use 1.3 Usage 8.5 Geriatric Use 2 DOSAGE AND ADMINISTRATION 8.6 Renal Impairment 2.1 Recommended Dosage 8.7 Hepatic Impairment 2.2 Dosage Adjustments in Patients with CLcr Less Than 10 OVERDOSAGE 60 mL/min (Including Patients Undergoing Intermittent HD or 11 DESCRIPTION CRRT), and CLcr 120 mL/min or Greater 12 CLINICAL PHARMACOLOGY 2.3 Preparation of FETROJA Solution for Administration 12.1 Mechanism of Action 2.4 Drug Compatibility 12.2 Pharmacodynamics 2.5 Storage of Reconstituted Solutions 12.3 Pharmacokinetics 3 DOSAGE FORMS AND STRENGTHS 12.4 Microbiology 4 CONTRAINDICATIONS 13 NONCLINICAL TOXICOLOGY 5 WARNINGS AND PRECAUTIONS 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 5.1 Increase in All-Cause Mortality in Patients with Carbapenem- 14 CLINICAL STUDIES Resistant Gram-Negative Bacterial Infections 14.1 Complicated Urinary Tract Infections, Including Pyelonephritis 5.2 Hypersensitivity Reactions 14.2 Hospital-acquired Bacterial Pneumonia and Ventilator- 5.3 Clostridioides difficile-associated Diarrhea (CDAD) associated Bacterial Pneumonia (HABP/VABP) 5.4 Seizures and Other Central Nervous System (CNS) Adverse 16 HOW SUPPLIED/STORAGE AND HANDLING Reactions 16.1 How Supplied 5.5 Development of Drug-Resistant Bacteria 16.2 Storage and Handling 6 ADVERSE REACTIONS 17 PATIENT COUNSELING INFORMATION 6.1 Clinical Trials Experience *Sections or subsections omitted from the full prescribing information are not listed.

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FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE 1.1 Complicated Urinary Tract Infections (cUTIs), Including Pyelonephritis FETROJA® is indicated in patients 18 years of age or older for the treatment of complicated urinary tract infections (cUTIs), including pyelonephritis caused by the following susceptible Gram-negative microorganisms: Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Pseudomonas aeruginosa, and Enterobacter cloacae complex [see Clinical Studies (14.1)].

1.2 Hospital-acquired Bacterial Pneumonia and Ventilator-associated Bacterial Pneumonia (HABP/VABP) FETROJA is indicated in patients 18 years of age or older for the treatment of hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia, caused by the following susceptible Gram-negative microorganisms: Acinetobacter baumannii complex, Escherichia coli, Enterobacter cloacae complex, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Serratia marcescens [see Clinical Studies (14.2)].

1.3 Usage To reduce the development of drug-resistant bacteria and maintain the effectiveness of FETROJA and other antibacterial drugs, FETROJA should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

2 DOSAGE AND ADMINISTRATION 2.1 Recommended Dosage The recommended dosage of FETROJA is 2 grams administered every 8 hours by intravenous (IV) infusion over 3 hours in adults with a creatinine clearance (CLcr) of 60 to 119 mL/min. Dosage adjustment of FETROJA is recommended for patients with CLcr less than 60 mL/min, including patients receiving intermittent hemodialysis (HD) or continuous renal replacement therapy (CRRT), and for patients with CLcr 120 mL/min or greater [see Dosage and Administration (2.2)]. The recommended duration of treatment with FETROJA is 7 to 14 days. The duration of therapy should be guided by the patient’s clinical status.

2.2 Dosage Adjustments in Patients with CLcr Less Than 60 mL/min (Including Patients Undergoing Intermittent HD or CRRT), and CLcr 120 mL/min or Greater Dosage Adjustments in Patients with CLcr Less Than 60 mL/min Including Patients Receiving Intermittent HD Dosage adjustment of FETROJA is recommended in patients with CLcr less than 60 mL/min (Table 1). For patients undergoing intermittent HD, start the dosing of FETROJA immediately after the completion of HD. For patients with fluctuating renal function, monitor CLcr and adjust dosage accordingly.

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Table 1 Recommended Dosage of FETROJA for Patients with CLcr Less Than 60 mL/min Including Patients Receiving Intermittent HD Infusion Estimated Creatinine Clearance (CLcr)a Dose Frequency Time CLcr 30 to 59 mL/min 1.5 grams Every 8 hours 3 hours CLcr 15 to 29 mL/min 1 gram Every 8 hours 3 hours CLcr less than 15 mL/min, with or without intermittent HDb 0.75 grams Every 12 hours 3 hours HD = hemodialysis. a CLcr = creatinine clearance estimated by Cockcroft-Gault equation. b Cefiderocol is removed by HD; administer FETROJA immediately after HD for patients receiving intermittent HD.

Dosage Adjustments in Patients Receiving CRRT For patients receiving CRRT, including continuous venovenous hemofiltration (CVVH), continuous venovenous hemodialysis (CVVHD) and continuous venovenous hemodiafiltration (CVVHDF), the dosage of FETROJA should be based on the effluent flow rate in CRRT (see Table 2). These recommendations are intended to provide initial dosing in patients receiving CRRT. Dosing regimens may need to be tailored based on residual renal function and patient’s clinical status [see Use in Specific Populations (8.6)].

Table 2 Recommended Dosage of FETROJA for Patients Receiving CRRT Effluent Flow Ratea Recommended Dosage of FETROJA 2 L/hr or less 1.5 grams every 12 hours 2.1 to 3 L/hr 2 grams every 12 hours 3.1 to 4 L/hr 1.5 grams every 8 hours 4.1 L/hr or greater 2 grams every 8 hours CRRT = continuous renal replacement therapy. a Ultrafiltrate flow rate for CVVH, dialysis flow rate for CVVHD, ultrafiltrate flow rate plus dialysis flow rate for CVVHDF.

Dosage Adjustments in Patients with CLcr 120 mL/min or Greater For patients with CLcr greater than or equal to 120 mL/min, FETROJA 2 grams administered every 6 hours by IV infusion over 3 hours is recommended [see Use in Specific Populations (8.6)].

2.3 Preparation of FETROJA Solution for Administration FETROJA is supplied as a sterile, lyophilized powder that must be reconstituted and subsequently diluted using aseptic technique prior to intravenous infusion. Preparation of Doses Reconstitute the powder for injection in the FETROJA vial with 10 mL of either 0.9% sodium chloride injection, USP or 5% dextrose injection, USP and gently shake to dissolve. Allow the vial(s) to stand until the foaming generated on the surface has disappeared (typically within 2 minutes). The final volume of the reconstituted solution will be approximately 11.2 mL. The reconstituted solution is for intravenous infusion only after dilution in an appropriate infusion solution. To prepare the required doses, withdraw the appropriate volume of reconstituted solution from the vial according to Table 3 below. Add the withdrawn volume to a 100 mL infusion bag containing 0.9% sodium chloride injection, USP or 5% dextrose injection, USP [see Dosage and Administration (2.4)].

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Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. FETROJA infusions are clear, colorless solutions. Discard any unused FETROJA solution in the vial (see Table 3).

Table 3 Preparation of FETROJA Doses Total Volume of FETROJA Number of 1-gram FETROJA Volume to Withdraw from Reconstituted Solution for FETROJA Vials to be Dose Reconstituted Vial(s) Further Dilution into a Reconstituted 100 mL Infusion Bag 2 grams 2 vials 11.2 mL (entire contents) of each vial 22.4 mL 11.2 mL (entire contents) of first vial 1.5 grams 2 vials 16.8 mL AND 5.6 mL from second vial 1 gram 1 vial 11.2 mL (entire contents) 11.2 mL 0.75 gram 1 vial 8.4 mL 8.4 mL

2.4 Drug Compatibility FETROJA solution for administration is compatible with: • 0.9% sodium chloride injection, USP • 5% dextrose injection, USP The compatibility of FETROJA solution for administration with solutions containing other drugs or other diluents has not been established.

2.5 Storage of Reconstituted Solutions Reconstituted FETROJA Upon reconstitution with the appropriate diluent, the reconstituted FETROJA solution in the vial should be immediately transferred and diluted into the infusion bag. Reconstituted FETROJA can be stored for up to 1 hour at room temperature in the vial. Discard any unused reconstituted solution. Diluted FETROJA Infusion Solution The diluted FETROJA infusion solution in the infusion bag is stable for up to 6 hours at room temperature. The diluted FETROJA infusion solution in the infusion bag may also be refrigerated at 2°C to 8°C (36°F to 46°F) for up to 24 hours, protected from light; and then the infusion should be completed within 6 hours at room temperature.

3 DOSAGE FORMS AND STRENGTHS FETROJA 1 gram for injection is supplied as a white to off-white, sterile, lyophilized powder for reconstitution in single-dose, clear glass vials; each vial contains 1 gram of cefiderocol.

4 CONTRAINDICATIONS FETROJA is contraindicated in patients with a known history of severe hypersensitivity to cefiderocol or other beta-lactam antibacterial drugs, or any other component of FETROJA [see Warnings and Precautions (5.2) and Adverse Reactions (6.1)].

Reference ID: 4676517

5 WARNINGS AND PRECAUTIONS 5.1 Increase in All-Cause Mortality in Patients with Carbapenem-Resistant Gram-Negative Bacterial Infections An increase in all-cause mortality was observed in patients treated with FETROJA as compared to best available therapy (BAT) in a multinational, randomized, open-label trial in critically ill patients with carbapenem-resistant Gram-negative bacterial infections (NCT02714595). Patients with nosocomial pneumonia, bloodstream infections, sepsis, or cUTI were included in the trial. BAT regimens varied according to local practices and consisted of 1 to 3 antibacterial drugs with activity against Gram-negative bacteria. Most of the BAT regimens contained colistin. The increase in all-cause mortality occurred in patients treated for nosocomial pneumonia, bloodstream infections, or sepsis. The 28-Day all-cause mortality was higher in patients treated with FETROJA than in patients treated with BAT [25/101 (24.8%) vs. 9/49 (18.4%), treatment difference 6.4%, 95% CI (-8.6, 19.2)]. All-cause mortality remained higher in patients treated with FETROJA than in patients treated with BAT through Day 49 [34/101 (33.7%) vs. 10/49 (20.4%), treatment difference 13.3%, 95% CI (-2.5, 26.9)]. Generally, deaths were in patients with infections caused by Gram-negative organisms, including nonfermenters such as Acinetobacter baumannii complex, Stenotrophomonas maltophilia, and Pseudomonas aeruginosa, and were the result of worsening or complications of infection, or underlying comorbidities. The cause of the increase in mortality has not been established. Closely monitor the clinical response to therapy in patients with cUTI and HABP/VABP.

5.2 Hypersensitivity Reactions Serious and occasionally fatal hypersensitivity (anaphylactic) reactions and serious skin reactions have been reported in patients receiving beta-lactam antibacterial drugs. Hypersensitivity was observed in FETROJA- treated patients in clinical trials [see Adverse Reactions (6.1)]. These reactions are more likely to occur in individuals with a history of beta-lactam hypersensitivity and/or a history of sensitivity to multiple allergens. There have been reports of individuals with a history of penicillin hypersensitivity who have experienced severe reactions when treated with cephalosporins. Before therapy with FETROJA is instituted, inquire about previous hypersensitivity reactions to cephalosporins, penicillins, or other beta-lactam antibacterial drugs. Discontinue FETROJA if an allergic reaction occurs.

5.3 Clostridioides difficile-associated Diarrhea (CDAD) Clostridioides difficile-associated diarrhea (CDAD) has been reported for nearly all systemic antibacterial agents, including FETROJA. CDAD may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of C. difficile. C. difficile produces toxins A and B, which contribute to the development of CDAD. Hypertoxin-producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial use. Careful medical history is necessary because CDAD has been reported to occur more than 2 months after the administration of antibacterial agents. If CDAD is suspected or confirmed, antibacterial drugs not directed against C. difficile may need to be discontinued. Manage fluid and electrolyte levels as appropriate, supplement protein intake, monitor antibacterial treatment of C. difficile, and institute surgical evaluation as clinically indicated.

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5.4 Seizures and Other Central Nervous System (CNS) Adverse Reactions Cephalosporins, including FETROJA, have been implicated in triggering seizures [see Adverse Reactions (6.1)]. Nonconvulsive status epilepticus (NCSE), encephalopathy, coma, asterixis, neuromuscular excitability, and myoclonia have been reported with cephalosporins particularly in patients with a history of epilepsy and/or when recommended dosages of cephalosporins were exceeded due to renal impairment. Adjust FETROJA dosing based on creatinine clearance [see Dosage and Administration (2.2)]. Anticonvulsant therapy should be continued in patients with known seizure disorders. If CNS adverse reactions including seizures occur, patients should undergo a neurological evaluation to determine whether FETROJA should be discontinued.

5.5 Development of Drug-Resistant Bacteria Prescribing FETROJA in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria [see Indications and Usage (1.3)].

6 ADVERSE REACTIONS The following serious adverse reactions are described in greater detail in the Warnings and Precautions section: • Increase in All-Cause Mortality in Patients with Carbapenem-Resistant Gram-Negative Bacterial Infections [see Warnings and Precautions (5.1)] • Hypersensitivity Reactions [see Warnings and Precautions (5.2)] • Clostridioides difficile-Associated Diarrhea (CDAD) [see Warnings and Precautions (5.3)] • Seizures and Other Central Nervous System Adverse Reactions [see Warnings and Precautions (5.4)]

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Complicated Urinary Tract Infections (cUTIs), Including Pyelonephritis FETROJA was evaluated in an active-controlled, randomized clinical trial in patients with cUTI, including pyelonephritis (Trial 1). In this trial, 300 patients received FETROJA 2 grams every 8 hours infused over 1 hour (or a renally-adjusted dose), and 148 patients were treated with imipenem/cilastatin 1 gram/1 gram every 8 hours infused over 1 hour (or a renally-adjusted dose). The median age of treated patients across treatment arms was 65 years (range 18 to 93 years), with approximately 53% of patients aged greater than or equal to 65. Approximately 96% of patients were White, most were from Europe, and 55% were female. Patients across treatment arms received treatment for a median duration of 9 days. Serious Adverse Reactions and Adverse Reactions Leading to Discontinuation In Trial 1, a total of 14/300 (4.7%) cUTI patients treated with FETROJA and 12/148 (8.1%) of cUTI patients treated with imipenem/cilastatin experienced serious adverse reactions. One death (0.3%) occurred in 300 patients treated with FETROJA as compared to none treated with imipenem/cilastatin. Discontinuation of treatment due to any adverse reaction occurred in 5/300 (1.7%) of patients treated with FETROJA and 3/148 (2.0%) of patients treated with imipenem/cilastatin. Specific adverse reactions leading to treatment discontinuation in patients who received FETROJA included diarrhea (0.3%), drug hypersensitivity (0.3%), and increased hepatic enzymes (0.3%).

Reference ID: 4676517

Common Adverse Reactions Table 4 lists the most common selected adverse reactions occurring in ≥ 2% of cUTI patients receiving FETROJA in Trial 1.

Table 4 Selected Adverse Reactions Occurring in ≥ 2% of cUTI Patients Receiving FETROJA in Trial 1 FETROJAa Imipenem/Cilastatinb Adverse Reaction (N = 300) (N = 148) Diarrhea 4% 6% Infusion site reactionsc 4% 5% Constipation 3% 4% Rashd 3% < 1% Candidiasise 2% 3% Cough 2% < 1% Elevations in liver testsf 2% < 1% Headache 2% 5% Hypokalemiag 2% 3% Nausea 2% 4% Vomiting 2% 1% cUTI = complicated urinary tract infection. a 2 grams IV over 1 hour every 8 hours (with dosing adjustment based on renal function). b 1 gram IV over 1 hour every 8 hours (with dosing adjustment based on renal function and body weight). c Infusion site reactions include infusion site erythema, inflammation, pain, pruritis, injection site pain, and phlebitis. d Rash includes rash macular, rash maculopapular, erythema, skin irritation. e Candidiasis includes oral or vulvovaginal candidiasis, candiduria. f Elevations in liver tests include alanine aminotransferase, aspartate aminotransferase, gamma-glutamyl transferase, blood alkaline phosphatase, hepatic enzyme increased. g Hypokalemia includes blood potassium decreased.

Other Adverse Reactions of FETROJA in the cUTI Patients (Trial 1) The following selected adverse reactions were reported in FETROJA-treated cUTI patients at a rate of less than 2% in Trial 1: Blood and lymphatic disorders: thrombocytosis Cardiac disorders: congestive heart failure, bradycardia, atrial fibrillation Gastrointestinal disorders: abdominal pain, dry mouth, stomatitis General system disorders: pyrexia, peripheral edema Hepatobiliary disorders: cholelithiasis, cholecystitis, gallbladder pain Immune system disorders: drug hypersensitivity Infections and infestations: C. difficile infection Laboratory investigations: prolonged prothrombin time (PT) and prothrombin time international normalized ratio (PT-INR), red blood cells urine positive, creatine phosphokinase increase Metabolism and nutrition disorders: decreased appetite, hypocalcemia, fluid overload

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Nervous system disorders: dysgeusia, seizure Respiratory, thoracic, and mediastinal disorders: dyspnea, pleural effusion Skin and subcutaneous tissue disorders: pruritis Psychiatric disorders: insomnia, restlessness

Hospital-acquired Bacterial Pneumonia and Ventilator-associated Bacterial Pneumonia (HABP/VABP) FETROJA was evaluated in an active-controlled clinical trial in patients with HABP/VABP (Trial 2). In this trial, 148 patients received FETROJA 2 grams every 8 hours infused over 3 hours, and 150 patients received meropenem 2 grams every 8 hours infused over 3 hours. Doses of study treatments were adjusted based on renal function. The median age was 67 years, approximately 59% of patients were 65 years of age and older, 69% were male, and 68% were White. Overall, approximately 60% were ventilated at randomization, including 41% with VABP and 14% with ventilated HABP. The mean Acute Physiology And Chronic Health Evaluation (APACHE II) score was 16. All patients received empiric treatment for Gram-positive organisms with linezolid for at least 5 days. Serious Adverse Reactions and Adverse Reactions Leading to Discontinuation In Trial 2, serious adverse reactions occurred in 54/148 (36.5%) HABP/VABP patients treated with FETROJA and 45/150 (30%) of HABP/VABP patients treated with meropenem. Adverse reactions leading to death were reported in 39/148 (26.4%) patients treated with FETROJA and 35/150 (23.3%) patients treated with meropenem. Adverse reactions leading to discontinuation of treatment occurred in 12/148 (8.1%) of patients treated with FETROJA and 14/150 (9.3%) of patients treated with meropenem. The most common adverse reactions leading to discontinuation in both treatment groups were elevated liver tests. Common Adverse Reactions Table 5 lists the most common selected adverse reactions occurring in ≥ 4% of patients receiving FETROJA in the HABP/VABP trial.

Table 5 Selected Adverse Reactions Occurring in ≥ 4% of HABP/VABP Patients Receiving FETROJA in Trial 2 FETROJAa Meropenemb Adverse Reaction N = 148 N = 150 Elevations in liver testsc 16% 16% Hypokalemiad 11% 15% Diarrhea 9% 9% Hypomagnesemia 5% < 1% Atrial fibrillation 5% 3% HABP/VABP = hospital-acquired bacterial pneumonia/ventilator-associated bacterial pneumonia. a 2 grams IV over 3 hours every 8 hours (with dosing adjustment based on renal function). b 2 grams IV over 3 hours every 8 hours (with dosing adjustment based on renal function). c Elevations in liver tests include the following terms: aspartate aminotransferase increased, alanine aminotransferase increased, gamma-glutamyl transferase increased, liver function test increased, liver function test abnormal, hepatic enzyme increased, transaminases increased, hypertransaminesemia. d Hypokalemia includes blood potassium decreased.

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Other Adverse Reactions of FETROJA in HABP/VABP Patients in Trial 2 The following selected adverse reactions were reported in FETROJA-treated HABP/VABP patients at a rate of less than 4% in Trial 2: Blood and lymphatic disorders: thrombocytopenia, thrombocytosis Cardiac disorders: myocardial infarction, atrial flutter Gastrointestinal disorders: nausea, vomiting, abdominal pain Hepatobiliary disorders: cholecystitis, cholestasis Infections and infestations: C. difficile infection, oral candidiasis Laboratory investigations: prolonged prothrombin time (PT) and prothrombin time international normalized ratio (PT-INR), and activated partial thromboplastin time (aPTT) Metabolism and nutrition disorders: hypocalcemia, hyperkalemia Nervous system disorders: seizure Renal and genitourinary disorders: acute interstitial nephritis Respiratory, thoracic, and mediastinal disorders: cough Skin and subcutaneous tissue disorders: rash including rash erythematous

7 DRUG INTERACTIONS 7.1 Drug/Laboratory Test Interactions Cefiderocol may result in false-positive results in dipstick tests (urine protein, ketones, or occult blood). Use alternate clinical laboratory methods of testing to confirm positive tests.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There are no available data on FETROJA use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Available data from published prospective cohort studies, case series, and case reports over several decades with cephalosporin use in pregnant women have not established drug-associated risks of major birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data). Developmental toxicity studies with cefiderocol administered during organogenesis to rats and mice showed no evidence of embryo-fetal toxicity, including drug-induced fetal malformations, at doses providing exposure levels 0.9 (rats) or 1.3 times (mice) higher than the average observed in patients receiving the maximum recommended daily dose. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

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Data Human Data While available studies cannot definitively establish the absence of risk, published data from prospective cohort studies, case series, and case reports over several decades have not identified an association with cephalosporin use during pregnancy and major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Available studies have methodologic limitations, including small sample size, retrospective data collection, and inconsistent comparator groups. Animal Data Developmental toxicity was not observed in rats at intravenous doses of up to 1000 mg/kg/day or mice at subcutaneous doses of up to 2000 mg/kg/day given during the period of organogenesis (gestation days 6-17 in rats and 6-15 in mice). No treatment-related malformations or reductions in fetal viability were observed. Mean plasma exposure (AUC) at these doses was approximately 0.9 times (rats) and 1.3 times (mice) the daily mean plasma exposure in patients that received 2 grams of cefiderocol infused intravenously every 8 hours. In a pre- and postnatal development study, cefiderocol was administered intravenously at doses up to 1000 mg/kg/day to rats from Day 6 of pregnancy until weaning. No adverse effects on parturition, maternal function, or pre- and postnatal development and viability of the pups were observed. In pregnant rats, cefiderocol-derived radioactivity was shown to cross the placenta, but the amount detected in fetuses was a small percentage (< 0.5%) of the dose.

8.2 Lactation Risk Summary It is not known whether cefiderocol is excreted into human milk; however, cefiderocol-derived radioactivity was detected in the milk of lactating rats that received the drug intravenously. When a drug is present in animal milk, it is likely that the drug will be present in human milk. No information is available on the effects of FETROJA on the breastfed infant or on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for FETROJA and any potential adverse effects on the breastfed child from FETROJA or from the underlying maternal condition. Data Cefiderocol-derived radioactivity was detected in milk following intravenous administration to lactating rats. The peak level in rat milk was approximately 6% of the peak plasma level.

8.4 Pediatric Use Safety and effectiveness of FETROJA in pediatric patients younger than 18 years of age have not been established.

8.5 Geriatric Use cUTI Of the 300 patients treated with FETROJA in the cUTI trial, 158 (52.7%) were 65 years of age and older, and 67 (22.3%) were 75 years of age and older. No overall differences in safety or efficacy were observed between these patients and younger patients.

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HABP/VABP Of the 148 patients treated with FETROJA in the HABP/VABP trial, 83 (56.1%) were 65 years of age and older, and 40 (27%) were 75 years of age and older. The incidence of adverse reactions in patients treated with FETROJA was similar in patients under 65 years of age as compared to older patients (65 years of age and older and 75 years of age and older). The incidence of adverse reactions in older patients (65 years of age and older and 75 years of age and older) was also similar between treatment groups. Clinical cure rates at the Test-of-Cure (TOC) visit in FETROJA-treated adult patients younger than 65 years of age, 65 years of age to younger than 75 years of age and 75 years of age and older were 60%, 77.5% and 60% respectively. In comparison, the clinical cure rates at the TOC visit in the meropenem-treated patients for each of these subgroups were 65.5%, 64.4% and 70.5%, respectively. The observed all-cause mortality rates at Day 14 in the FETROJA-treated patients for each of these subgroups were 12.3%, 7.5% and 17.5%, respectively. In comparison, in the meropenem-treated patients for each of these subgroups, they were 10.3%, 17.8% and 9.1%, respectively. cUTI and HABP/VABP FETROJA is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function. No dosage adjustment is required based on age. Dosage adjustment for elderly patients should be based on renal function [see Dosage and Administration (2.2), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3)].

8.6 Renal Impairment Patients with CLcr 60 to 89 mL/min No dosage adjustment of FETROJA is recommended in patients with CLcr 60 to 89 mL/min. Patients with CLcr Less Than 60 mL/min Including Patients Receiving Intermittent HD Dose adjustment is required in patients with CLcr less than 60 mL/min, and in patients who are receiving HD. In patients requiring HD, complete HD at the latest possible time before the start of cefiderocol dosing [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)]. Monitor renal function regularly and adjust the dosage of FETROJA accordingly as renal function may change during the course of therapy. Patients Receiving CRRT A total of 16 patients treated with FETROJA received CRRT in clinical trials. Dosage adjustment of FETROJA is required in patients receiving CRRT including CVVH, CVVHD and CVVHDF. Dosage of FETROJA should be based on the effluent flow rate in patients receiving CRRT [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)]. While on CRRT, a patient’s residual renal function may change. Improvements or reductions in residual renal function may warrant a change in FETROJA dosage. Patients with CLcr 120 mL/min or greater CLcr 120 mL/min or greater may be seen in seriously ill patients, who are receiving intravenous fluid resuscitation. Dosage adjustment of FETROJA is required in patients with CLcr 120 mL/min or greater [see Dosage and Administration (2.2) and Clinical Pharmacology (12.3)]. Monitor renal function regularly and adjust the dosage of FETROJA accordingly as renal function may change during the course of therapy.

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8.7 Hepatic Impairment The effects of hepatic impairment on the pharmacokinetics of cefiderocol have not been evaluated. Hepatic impairment is not expected to alter the elimination of cefiderocol as hepatic metabolism/excretion represents a minor pathway of elimination for cefiderocol. Dosage adjustments are not necessary in patients with impaired hepatic function.

10 OVERDOSAGE There is no information on clinical signs and symptoms associated with an overdose of FETROJA. Patients who receive doses greater than the recommended dose regimen and have unexpected adverse reactions possibly associated with FETROJA should be carefully observed and given supportive treatment, and discontinuation or interruption of treatment should be considered. Approximately 60% of cefiderocol is removed by a 3- to 4-hour hemodialysis session [see Clinical Pharmacology (12.3)].

11 DESCRIPTION FETROJA is a cephalosporin antibacterial drug product consisting of cefiderocol sulfate tosylate for intravenous infusion. Cefiderocol functions as a siderophore [see Microbiology (12.4)]. The chemical name of cefiderocol sulfate tosylate is Tris[(6R,7R)-7-[(2Z)-2-(2-amino-1,3-thiazol-4-yl)-2-{[(2- carboxypropan-2-yl)oxy]imino}acetamido]-3-({1-[2-(2-chloro-3,4-dihydroxybenzamido)ethyl]pyrrolidin-1- ium-1-yl}methyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate] tetrakis(4-methylbenzenesulfonate) monosulfate hydrate, and the molecular weight is 3043.50 (anhydrous). The molecular formula is 3C30H34ClN7O10S2•4C7H8O3S•H2SO4•xH2O.

Figure 1 Chemical Structure of Cefiderocol Sulfate Tosylate

OH H3C CO2H Cl OH H3C CO2 SO3H O H O + N • • • N N N H2SO4 xH2O H H C N N O 3 S H2N H H O 3 4 S

FETROJA for injection is a white to off-white, sterile, lyophilized powder formulated with 1 gram of cefiderocol (equivalent to 1.6 grams of cefiderocol sulfate tosylate), sucrose (900 mg), sodium chloride (216 mg), and sodium hydroxide to adjust pH. The sodium content is approximately 176 mg/vial. The pH of the reconstituted solution of 1 gram cefiderocol (1 vial) dissolved in 10 mL water is 5.2 to 5.8.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action FETROJA is an antibacterial drug [see Microbiology (12.4)].

12.2 Pharmacodynamics The percent time of dosing interval that unbound plasma concentrations of cefiderocol exceed the minimum inhibitory concentration (MIC) against the infecting organism best correlates with antibacterial activity in neutropenic murine thigh and lung infection models with E. coli, K. pneumoniae, P. aeruginosa, A. baumannii, and S. maltophilia. Compared to a 1-hour infusion, a 3-hour infusion increased the percent time of dosing interval that unbound plasma concentrations of cefiderocol exceed the MIC. The in vivo animal pneumonia 12

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studies showed that the antibacterial activity of cefiderocol was greater at the human equivalent dosing regimen of 3-hour infusion compared to that of 1-hour infusion. Cardiac Electrophysiology At doses 1 and 2 times the maximum recommended dosage, FETROJA does not prolong the QT interval to any clinically relevant extent.

12.3 Pharmacokinetics

Cefiderocol exposures (Cmax and daily AUC) in cUTI patients, HABP/VABP patients and healthy volunteers are summarized in Table 6. Cefiderocol Cmax and AUC increased proportionally with dose.

Table 6 Cefiderocol Exposures Mean (±SD) in Patients and Healthy Volunteers with CLcr 60 mL/min or Greater cUTI Patientsa HABP/VABP Patientsa Healthy Volunteersb PK Parameters (N = 21) (N = 146) (N = 43)

Cmax (mg/L) 115 (±57) 111 (±56) 91.4 (±17.9)

AUC0-24 hrs (mg·hr/L) 1944 (±1097) 1773 (±990) 1175 (±203)

Cmax = maximum concentration.

AUC0-24 hrs = area under the concentration time curve from 0 to 24 hours. a After multiple (every 8 hours) FETROJA 2-gram doses infused over 3 hours or adjusted based on renal function. b After a single FETROJA 2-gram dose was infused over 3 hours.

Distribution The geometric mean (±SD) cefiderocol volume of distribution was 18.0 (± 3.36) L. Plasma protein binding, primarily to albumin, of cefiderocol is 40% to 60%. Following a FETROJA 2-gram dose (or renal function equivalent dose) at steady state in patients with pneumonia requiring mechanical ventilation with a 3-hour infusion, the cefiderocol concentrations in epithelial lining fluid ranged 3.1 to 20.7 mg/L and 7.2 to 15.9 mg/L at the end of infusion and at 2 hours after the end of infusion, respectively. Elimination Cefiderocol terminal elimination half-life is 2 to 3 hours. The geometric mean (± SD) cefiderocol clearance is estimated to be 5.18 (± 0.89) L/hr. Metabolism Cefiderocol is minimally metabolized [less than 10% of a single radiolabeled cefiderocol dose of 1 gram (0.5 times the approved recommended dosage) infused over 1 hour]. Excretion Cefiderocol is primarily excreted by the kidneys. After a single radiolabeled cefiderocol 1-gram (0.5 times the approved recommended dosage) dose infused over 1 hour, 98.6% of the total radioactivity was excreted in urine (90.6% unchanged) and 2.8% in feces. Specific Populations No clinically significant differences in the pharmacokinetics of cefiderocol were observed based on age (18 to 93 years of age), sex, or race. The effect of hepatic impairment on the pharmacokinetics of cefiderocol was not evaluated.

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Patients with Renal Impairment Approximately 60% of cefiderocol was removed by a 3- to 4-hour hemodialysis session. Cefiderocol AUC fold changes in subjects with renal impairment compared to subjects with CLcr 90 to 119 mL/min are summarized in Table 7.

Table 7 Effect of Renal Impairment on the AUC of Cefiderocola Cefiderocol AUC CLcr (mL/min) Geometric Mean Ratios (90% CI)b 60 to 89 (N = 6) 1.37 (1.15, 1.62) 30 to 59 (N = 7) 2.35 (2.00, 2.77) 15 to 29 (N = 4) 3.21 (2.64, 3.91) < 15 (N = 6) 4.69 (3.95, 5.56) CI = confidence interval. a After a single FETROJA 1-gram dose (0.5 times the approved recommended dosage). b Compared to AUC in subjects with CLcr 90 to 119 mL/min (N = 12).

Patients Receiving CRRT In an in vitro study, effluent flow rate was the major determinant of cefiderocol clearance by CRRT. Variables examined included effluent flow rate, CRRT mode (CVVH or CVVHD), filter type and point of dilution (pre- or post-filter dilution). The effluent flow rate-based dosing recommendations in Table 2 are predicted to provide cefiderocol exposures similar to those achieved with a dose of 2 grams given every 8 hours in patients not receiving CRRT [see Dosage and Administration (2.2)]. Patients with CLcr 120 mL/min or Greater Increased cefiderocol clearance has been observed in patients with CLcr 120 mL/min or greater. A FETROJA 2-gram dose every 6 hours infused over 3 hours provided cefiderocol exposures comparable to those in patients with CLcr 90 to 119 mL/min [see Dosage and Administration (2.2)]. Drug Interaction Studies Clinical Studies No clinically significant differences in the pharmacokinetics of furosemide (an organic anion transporter [OAT]1 and OAT3 substrate), metformin (an organic cation transporter [OCT]1, OCT2, and multidrug and toxin extrusion [MATE]2-K substrate), and rosuvastatin (an organic anion transporting polypeptide [OATP]1B3 substrate) were observed when coadministered with cefiderocol. In Vitro Studies Where Drug Interaction Potential Was Not Further Evaluated Clinically Cytochrome P450 (CYP) Enzymes: Cefiderocol is not an inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, or CYP3A4. Cefiderocol is not an inducer of CYP1A2, CYP2B6, or CYP3A4. Transporter Systems: Cefiderocol is not an inhibitor of OATP1B1, MATE1, P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), or bile salt export pump transporters. Cefiderocol is not a substrate of OAT1, OAT3, OCT2, MATE1, MATE2-K, P-gp, or BCRP.

12.4 Microbiology Mechanism of Action FETROJA is a cephalosporin antibacterial with activity against Gram-negative aerobic bacteria. Cefiderocol functions as a siderophore and binds to extracellular free (ferric) iron. In addition to passive diffusion via porin 14

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channels, cefiderocol is actively transported across the outer cell membrane of bacteria into the periplasmic space using the bacterial siderophore iron uptake mechanism. Cefiderocol exerts bactericidal action by inhibiting cell wall biosynthesis through binding to penicillin-binding proteins (PBPs). Cefiderocol has no clinically relevant in vitro activity against most Gram-positive bacteria and anaerobic bacteria. Resistance In vitro, MIC increases that may result in resistance to cefiderocol in Gram-negative bacteria have been associated with a combination of multiple beta-lactamases, modifications of PBPs, and mutations of transcriptional regulators that impact siderophore expression. Cefiderocol does not cause induction of AmpC beta-lactamase in P. aeruginosa and E. cloacae. The frequency of resistance development in Gram-negative bacteria including carbapenemase producers exposed to cefiderocol at 10x minimum inhibitory concentration (MIC) ranged from 10-6 to < 10-8. Cross-resistance with other classes of antibacterial drugs has not been identified; therefore, isolates resistant to other antibacterial drugs may be susceptible to cefiderocol. Cefiderocol has shown in vitro activity against isolates of S. maltophilia and a subset of isolates of Enterobacterales and P. aeruginosa that are resistant to meropenem, ciprofloxacin, amikacin, cefepime, ceftazidime-avibactam, and ceftolozane/tazobactam. Cefiderocol has shown in vitro activity against subset of isolates of A. baumannii complex that are resistant to meropenem, ciprofloxacin, and amikacin. Cefiderocol is active against some colistin-resistant E. coli isolates containing mcr-1. Cefiderocol demonstrated in vitro activity against a subgroup of Enterobacterales genetically confirmed to contain the following: ESBLs (TEM, SHV, CTX-M, oxacillinase [OXA]), AmpC, AmpC-type ESBL (CMY), serine-carbapenemases (such as KPC, OXA-48), and metallo-carbapenemases (such as NDM and VIM). Cefiderocol demonstrated in vitro activity against a subgroup of P. aeruginosa genetically confirmed to contain VIM, IMP, GES, AmpC and a subgroup of A. baumannii containing OXA-23, OXA-24/40, OXA-51, OXA-58 and AmpC. Cefiderocol is active in vitro against a subgroup of S. maltophilia containing metallo- carbapenemase (L1) and serine beta-lactamases (L2). Cefiderocol maintained in vitro activity against K. pneumoniae in the presence of porin channel deletions (OmpK35/36), and against P. aeruginosa in the presence of porin channel deletions (OprD) and efflux pump up-regulation (MexAB-OprM, MexCD-OprJ, MexEF-OprN, and MexXY). In vitro, the addition of the beta-lactamase inhibitors (such as avibactam, clavulanic acid, and dipicolinic acid) results in the lowering of MICs of some clinical isolates with relatively high MICs (range 2 to 256 mcg/mL) to cefiderocol. Interaction with Other Antimicrobials In vitro studies showed no antagonism between cefiderocol and amikacin, ceftazidime/avibactam, ceftolozane/tazobactam, ciprofloxacin, clindamycin, colistin, daptomycin, linezolid, meropenem, metronidazole, tigecycline, or vancomycin against strains of Enterobacterales, P. aeruginosa, and A. baumannii. Activity against Bacteria in Animal Infection Models In a neutropenic murine thigh infection model using a humanized dose (2 grams every 8 hours), cefiderocol demonstrated 1log10 reduction in bacterial burden against most E. coli, K. pneumoniae, A. baumannii, S. maltophilia, and P. aeruginosa including some carbapenemase-producing (KPC, OXA-23, OXA-24/40, OXA-58) isolates with MICs of ≤ 4 mcg/mL to cefiderocol. In an immunocompetent rat pneumonia model, reduction in bacterial counts in the lungs of animals infected with K. pneumoniae with MICs ≤ 8 mcg/mL, A. baumannii with MICs ≤ 2 mcg/mL, and P. aeruginosa with

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MICs ≤ 1 mcg/mL including carbapenemase (KPC, NDM and IMP) producing isolates was observed using humanized cefiderocol drug exposure. In an immunocompetent murine urinary tract infection model, cefiderocol reduced bacterial counts in the kidneys of mice infected with E. coli, K. pneumoniae, and P. aeruginosa isolates with MICs ≤ 1 mcg/mL. In an immunocompromised murine systemic infection model, cefiderocol increased survival in mice infected with E. cloacae, S. maltophilia, and Burkholderia cepacia isolates with MICs ≤ 0.5 mcg/mL compared to untreated mice. In an immunocompetent murine systemic infection model, cefiderocol increased survival in mice infected with S. marcescens and P. aeruginosa isolates with MICs ≤ 1 mcg/mL compared to untreated mice. The clinical significance of the above findings in animal infection models is not known. Antimicrobial Activity FETROJA has been shown to be active against the following bacteria, both in vitro and in clinical infections [see Indications and Usage (1)]. Complicated Urinary Tract Infections, Including Pyelonephritis Gram-negative bacteria Escherichia coli Enterobacter cloacae complex Klebsiella pneumoniae Proteus mirabilis Pseudomonas aeruginosa Hospital-acquired Bacterial Pneumonia and Ventilator-associated Bacterial Pneumonia (HABP/VABP) Gram-negative bacteria Acinetobacter baumannii complex Escherichia coli Enterobacter cloacae complex Klebsiella pneumoniae Pseudomonas aeruginosa Serratia marcescens The following in vitro data are available, but their clinical significance is not known. At least 90% of the following bacteria exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for FETROJA against isolates of similar genus or organism group. However, the efficacy of FETROJA in treating clinical infections caused by these bacteria has not been established in adequate and well-controlled clinical trials. Gram-negative bacteria Achromobacter spp. Burkholderia cepacia complex Citrobacter freundii complex Citrobacter koseri Klebsiella aerogenes

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Klebsiella oxytoca Morganella morganii Proteus vulgaris Providencia rettgeri Stenotrophomonas maltophilia Susceptibility Testing For specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by FDA for this drug, please see https://www.fda.gov/STIC.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis Carcinogenicity studies in animals have not been conducted with cefiderocol. Mutagenesis Cefiderocol was negative for genotoxicity in a reverse mutation test with S. typhimurium and E. coli and did not induce mutations in V79 Chinese hamster lung cells. Cefiderocol was positive in a chromosomal aberration test in cultured TK6 human lymphoblasts and increased mutation frequency in L5178Y mouse lymphoma cells. Cefiderocol was negative in an in vivo rat micronucleus test and a rat comet assay at the highest doses of 2000 and 1500 mg/kg/day, respectively. Impairment of Fertility Cefiderocol did not affect fertility in adult male or female rats when administered intravenously at doses up to 1000 mg/kg/day. The AUC at this dose is approximately 0.9 times the mean daily cefiderocol exposure in patients who received the maximum recommended clinical dose of 2 grams every 8 hours.

14 CLINICAL STUDIES 14.1 Complicated Urinary Tract Infections, Including Pyelonephritis A total of 448 adults hospitalized with cUTI (including pyelonephritis) were randomized in a 2:1 ratio and received study medications in a multinational, double-blind trial (Trial 1) (NCT02321800) comparing FETROJA 2 grams intravenously (IV) every 8 hours (infused over 1 hour) to imipenem/cilastatin 1gram/1gram IV every 8 hours (infused over 1 hour) for 7 to 14 days. No switch from IV to oral antibacterial therapy was permitted. Efficacy was assessed as a composite of microbiological eradication and clinical cure at the Test of Cure (TOC) visit in the microbiological intent-to-treat (Micro-ITT) population, which included all patients who received at least a single dose of study medication and had at least one baseline Gram-negative uropathogen. Other efficacy endpoints included the microbiological eradication rate and the clinical response rate at TOC in the Micro-ITT population. The Micro-ITT population consisted of 371 patients of whom 25% had cUTI with pyelonephritis, 48% had cUTI without pyelonephritis, and 27% had acute uncomplicated pyelonephritis. Complicating conditions included obstructive uropathy, catheterization, and renal stones. The median age was 66 years, with 24% of patients over the age of 75 years, and 55% of the population were female. The median duration of therapy in both treatment groups was 9 days (range: 1-14 days). Of the 371 patients, 32% had CLcr > 50-80 mL/min, 17% had CLcr 30-50 mL/min, and 3% had CLcr < 30 mL/min at baseline. Concomitant Gram-negative bacteremia

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was identified in 7% of patients. In the Micro-ITT population, the most common baseline pathogens were E. coli and K. pneumoniae. Table 8 provides the results of a composite of microbiological eradication (all Gram-negative uropathogens found at baseline at ≥ 105 CFU/mL reduced to < 104 CFU/mL) and clinical response (resolution or improvement of cUTI symptoms and no new symptoms assessed by the investigator) at the TOC visit, 7 +/- 2 days after the last dose of study drug. The response rates for the composite endpoint of microbiological eradication and clinical response at the TOC visit were higher in the FETROJA arm compared with imipenem/cilastatin, as shown in Table 9. Clinical response rates at the TOC visit were similar between FETROJA and imipenem/cilastatin. Most patients with microbiological failure at the TOC visit in either treatment arm did not require further antibacterial drug treatment. Subgroup analyses examining composite outcomes by baseline pathogen are shown in Table 8 and demonstrated responses consistent with the overall population. Subgroup analyses examining outcomes by age, gender, and/or outcomes in patients with renal impairment, concomitant bacteremia, complicated UTI with or without pyelonephritis, or acute uncomplicated pyelonephritis demonstrated responses were consistent with the overall population.

Table 8 Composite, Microbiological, and Clinical Response Rates at the TOC Visit in cUTI Patients (Micro-ITT Population) in Trial 1 FETROJA Imipenem/Cilastatin Treatment Difference Study Endpoint n/N (%) n/N (%) (95% CI)a Composite response at TOC 183/252 (72.6%) 65/119 (54.6%) 18.6 (8.2, 28.9) Microbiologic response TOC 184/252 (73.0%) 67/119 (56.3%) 17.3 (6.9, 27.6) Clinical response TOC 226/252 (89.7%) 104/119 (87.4%) 2.4 (-4.7, 9.4) CI = confidence interval; Micro-ITT = microbiological intent-to-treat; TOC = Test of Cure. a The treatment difference and 95% CI were based on the Cochran-Mantel-Haenszel method.

Table 9 Composite Endpoint of Microbiological Eradication and Clinical Response at the TOC Visit in cUTI Patients (Micro-ITT Population) by Baseline Pathogena Subgroups FETROJA Imipenem/Cilastatin Baseline Pathogen Subgroup n/N (%) n/N (%) Escherichia coli 113/152 (74.3) 45/79 (57.0) Klebsiella pneumoniae 36/48 (75.0) 12/25 (48.0) Proteus mirabilis 13/17 (76.5) 0/2 (0.0) Pseudomonas aeruginosa 8/18 (44.4) 3/5 (60.0) Enterobacter cloacae complex 8/13 (61.5) 3/3 (100.0) a Patients may have had more than one pathogen in the baseline urine culture.

In the FETROJA treatment group, 61 (24.2%) bacterial isolates were ESBL producers compared with 32 (26.9%) in the imipenem/cilastatin group. The composite response rate of patients with these ESBL isolates at the TOC visit was consistent with the overall results.

14.2 Hospital-acquired Bacterial Pneumonia and Ventilator-associated Bacterial Pneumonia (HABP/VABP) A total of 298 hospitalized adults with HABP/VABP received study medications in a multicenter, randomized, double-blind trial (Trial 2) (NCT03032380) comparing FETROJA 2 grams administered intravenously every 8 hours as a 3-hour infusion to meropenem (2 grams every 8 hours infused over 3 hours). Dosing was adjusted for renal function. Patients in both treatment arms received linezolid 600 mg every 12 hours for at least 5 days

Reference ID: 4676517

for empiric treatment of Gram-positive organisms. The trial protocol permitted administration of potentially active prior antibacterial therapy for no more than 24 hours within 72 hours prior to randomization and disallowed systemic concomitant antibacterial therapy until the test-of-cure visit (TOC, 7 days after end of treatment). The analysis population was the modified intent-to-treat (mITT) population, which included all randomized patients who received study medication and had evidence of bacterial pneumonia, except those with only anaerobic or Gram-positive aerobic infections. Of the 292 patients in the mITT population, the median age was 67 years, and 58% of the population was 65 years of age and older, with 29% of the population 75 years of age and older. The majority of patients were male (68%), White (69%), and were from Europe (67%). Approximately 4% (11/292) were from the United States. The median baseline APACHE II score was 15, and 29% of patients had a baseline APACHE II score of greater than or equal to 20. At randomization, 68% of patients were in the ICU, and 60% were mechanically ventilated. 60% of patients had CLcr less than or equal to 80 mL/min at baseline; among these, 34% had CLcr less than or equal to 50 mL/min, and 14% had a CLcr less than 30 mL/min. Augmented renal clearance (CLcr greater than 120 mL/min) was present in 16% of patients. Gram-negative bacteremia was present at baseline in 6% of patients. In both treatment groups, most patients (70%) received between 7 and 14 days of study medication and 18% between 15 and 21 days. Table 10 shows the Day 14 and Day 28 all-cause mortality rates, as well as clinical cure at the TOC visit. FETROJA was noninferior to meropenem with regard to the primary efficacy endpoint (Day 14 all-cause mortality in the mITT population). Clinical cure was defined as resolution or substantial improvement in signs and symptoms associated with pneumonia, such that no additional antibacterial therapy was required for the treatment of the current infection through the TOC visit.

Table 10 All-cause Mortality and Clinical Cure at the TOC Visit in HABP/VABP Patients (mITT Population) in Trial 2 Treatment FETROJA Meropenem Endpoint Differencea n/N (%) n/N (%) (95% CI) Day 14 All-cause Mortality 18/145 (12.4) 18/147 (12.2) 0.2 (-7.2, 7.7) Day 28 All-cause Mortality 32/145 (22.1) 31/147 (21.1) 1.1 (-8.2, 10.4) Clinical Cure at TOC 94/145 (64.8) 98/147 (66.7) -2.0 (-12.5, 8.5) CI = confidence interval; TOC = Test of Cure. a The adjusted treatment difference (FETROJA minus meropenem) and associated 95% CI were based on the Cochran-Mantel- Haenszel stratum-weighted method. Subjects with unknown survival status were considered deaths. For Day 14 All-cause Mortality, 1 meropenem subject had unknown status; for Day 28 All-cause Mortality, 1 meropenem subject and 2 FETROJA subjects had unknown status.

The Day 14 and Day 28 all-cause mortality rates by pathogen in patients in the mITT population who had a baseline LRT pathogen that was susceptible to meropenem are shown in Table 11; the clinical outcome at the TOC visit is shown in Table 12. There were 51 patients with A. baumannii complex at baseline, of which 17 (33.3%) patients had isolates susceptible to meropenem (MIC ≤ 8 mcg/mL, based on meropenem 2 grams every 8 hours). Among 51 patients with A. baumannii complex at baseline, all-cause mortality at Day 14 was 5/26 (19.2%) in FETROJA and 4/25 (16.0%) in the meropenem treatment group and at Day 28 was 9/26 (34.6%) in FETROJA and 6/25 (24.0%) in the meropenem treatment group. The clinical cure rates at the TOC visit were 14/26 (53.8%) in the FETROJA and 15/25 (60.0%) in the meropenem treatment group.

Reference ID: 4676517

Table 11 All-cause Mortality by Baseline Pathogens Susceptible to Meropenem* in HABP/VABP Patients (mITT Population) in Trial 2 Day 14 All-cause Mortality Day 28 All-cause Mortality Baseline Pathogen FETROJA Meropenem FETROJA Meropenem n/N (%) n/N (%) n/N (%) n/N (%) Klebsiella pneumoniae 4/38 (10.5) 4/36 (11.1) 8/38 (21.1) 9/36 (25.0) Pseudomonas aeruginosa 2/20 (10.0) 4/17 (23.5) 2/20 (10.0) 5/17 (29.4) Acinetobacter baumannii complexa 1/8 (12.5) 0/9 (0.0) 3/8 (37.5) 0/9 (0.0) Escherichia coli 3/18 (16.7) 3/21 (14.3) 5/18 (27.8) 4/21 (19.0) Other Enterobacteralesb 2/16 (12.5) 2/14 (14.3) 4/16 (25.0) 3/14 (21.4) Each cell excludes subjects in whom baseline pathogen had meropenem MIC > 8 mcg/mL or where MIC was unknown. Subjects with unknown survival status were considered deaths. * Susceptible defined as MIC of ≤ 8 mcg/mL to meropenem. a Includes A. baumannii, A. nosocomialis, and A. pittii. b Includes Enterobacter cloacae complex (E. cloacae, E. asburiae and E. kobei) and Serratia marcescens.

Table 12 Clinical Cure Rates by Baseline Pathogen Susceptible to Meropenem* at the TOC Visit in HABP/VABP (mITT Population) in Trial 2 Clinical Cure Baseline Pathogen FETROJA Meropenem n/N (%) n/N (%) Klebsiella pneumoniae 24/38 (63.2) 23/36 (63.9) Pseudomonas aeruginosa 13/20 (65.0) 13/17 (76.5) Acinetobacter baumannii complexa 6/8 (75.0) 7/9 (77.8) Escherichia coli 12/18 (66.7) 13/21 (61.9) Other Enterobacteralesb 10/16 (62.5) 8/14 (57.1) Each cell excludes subjects whose pathogen-specific meropenem MIC > 8 mcg/mL or where MIC was unknown. * Susceptible defined as MIC of ≤ 8 mcg/mL to meropenem. a Includes A. baumannii, A.nosocomialis, and A. pittii. b Includes Enterobacter cloacae complex (E. cloacae, E. asburiae and E. kobei) and Serratia marcescens.

In the FETROJA treatment group, 45 (31%) patients had ESBL-producing bacterial isolates compared with 42 (28.6%) patients in the meropenem treatment group. All-cause mortality at Day 14 and Day 28 of patients with these ESBL-producing bacterial isolates was consistent with the overall results.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied FETROJA 1 gram (cefiderocol) for injection is supplied as a white to off-white sterile lyophilized powder for reconstitution in single-dose, clear glass vials (NDC 59630-266-01) sealed with a rubber stopper (not made with natural rubber latex) and an aluminum seal with flip-off cap. Each vial is supplied in cartons containing 10 single-dose vials. NDC 59630-266-10 FETROJA (cefiderocol) 1 gram/vial, 10 vials/carton

Reference ID: 4676517

16.2 Storage and Handling FETROJA vials should be stored refrigerated at 2°C to 8°C (36°F to 46°F). Protect from light. Store in the carton until time of use. Store reconstituted solutions of FETROJA at room temperature [see Dosage and Administration (2.5)].

17 PATIENT COUNSELING INFORMATION Serious Allergic Reactions Advise patients and their families that allergic reactions, including serious allergic reactions, could occur with FETROJA and that serious reactions require immediate treatment. Ask patients about any previous hypersensitivity reactions to FETROJA, other beta-lactams (including cephalosporins), or other allergens [see Warnings and Precautions (5.2)]. Potentially Serious Diarrhea Advise patients and their families that diarrhea is a common problem caused by antibacterial drugs, including FETROJA. Sometimes, frequent watery or bloody diarrhea may occur and may be a sign of a more serious intestinal infection. If severe watery or bloody diarrhea develops, tell patient to contact his or her healthcare provider [see Warnings and Precautions (5.3)]. Seizures Counsel patients on the implication of cephalosporins, including FETROJA, in triggering seizures, particularly in patients with renal impairment when the dosage was not reduced and in patients with a history of epilepsy [see Warnings and Precautions (5.4)]. Antibacterial Resistance Patients should be counseled that antibacterial drugs including FETROJA should only be used to treat bacterial infections. They do not treat viral infections (e.g., influenza, common cold). When FETROJA is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by FETROJA or other antibacterial drugs in the future [see Warnings and Precautions (5.5)].

Manufactured by Shionogi & Co., Ltd. Osaka 541-0045 Japan

Manufactured for Shionogi Inc. Florham Park, NJ USA, 07932

SUMATHI NAMBIAR 09/25/2020 05:55:24 PM

( Reference ID: 4676517

CENTER FOR DRUG EVALUATION AND RESEARCH

APPLICATION NUMBER:

209445Orig1s002

MULTI-DISCIPLINE REVIEW Summary Review Office Director Cross Discipline Team Leader Review Clinical Review Non-Clinical Review Statistical Review Clinical Pharmacology Review NDA 209445 / S-002 Cefiderocol (Fetroja)

Integrated Review Table 1. Administrative Application Information Category Application Information Application type Efficacy Supplement Application number(s) NDA 209445/S-002 Priority or standard Priority Submit date(s) 3/27/2020 Received date(s) 3/27/2020 PDUFA goal date 9/27/2020 Division Division of Anti-Infectives (DAI) Review completion date 8/14/2020 Established name Cefiderocol Trade name Fetroja Pharmacologic class Cephalosporin Code name S-649266 Applicant Shionogi, Inc. Dose form/formulation(s) Intravenous Dosing regimen 2 gm every 8 hours (2 vials of 1 gm every 8 hours) Applicant proposed FETROJA is indicated in patients 18 years of age or older for the indication(s)/population(s) treatment of hospital-acquired bacterial pneumonia and ventilator- associated bacterial pneumonia, caused by the following susceptible Gram-negative microorganisms: Acinetobacter baumannii complex, Burkholderia cepacia complex, (b) (4) Escherichia coli, Enterobacter cloacae complex, (b) (4) , Klebsiella pneumoniae, (b) (4) Pseudomonas aeruginosa, Serratia marcescens, and (b) (4) Proposed SNOMED 425464007: Hospital-acquired Bacterial pneumonia indication 429271009: Ventilator-associated Bacterial pneumonia Regulatory action Approval Approved FETROJA is indicated in patients 18 years of age or older for the indication(s)/population(s) treatment of hospital-acquired bacterial pneumonia and ventilator- (if applicable) associated bacterial pneumonia, caused by the following susceptible Gram-negative microorganisms: Acinetobacter baumannii complex, Escherichia coli, Enterobacter cloacae complex, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Serratia marcescens. Approved SNOMED 425464007: Hospital-acquired Bacterial pneumonia indication 429271009: Ventilator-associated Bacterial pneumonia

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Reference ID: 4676324 NDA 209445 / S-002 Cefiderocol (Fetroja) Table of Contents Table of Tables ...... v Table of Figures ...... ix Glossary ...... 1 I. Executive Summary ...... 5 1. Summary of Regulatory Action ...... 5 2. Benefit-Risk Assessment ...... 7 II. Interdisciplinary Assessment ...... 12 3. Introduction ...... 12 3.1. Approach to the Review ...... 13 4. Patient Experience Data ...... 15 5. Pharmacologic Activity, Pharmacokinetics, and Clinical Pharmacology ...... 16 5.1. Nonclinical Assessment of Potential Effectiveness ...... 18 6. Evidence of Benefit (Assessment of Efficacy)...... 19 6.1. Assessment of Dose and Potential Effectiveness ...... 19 6.2. Design of Clinical Trials Intended to Demonstrate Benefit to Patients ...... 21 6.2.1. Trial Design ...... 21 6.2.2. Eligibility Criteria ...... 21 6.2.3. Statistical Analysis Plan ...... 22 6.3. Results of Analyses of Clinical Trials/Studies Intended to Demonstrate Benefit to Patients ...... 23 6.4. Review Issues Relevant to the Evaluation of Benefit ...... 29 6.4.1. Important Review Issue #1 Relevant to Benefit ...... 29 6.4.2. Important Review Issue #2 Relevant to Benefit ...... 30 6.4.3. Important Review Issue #3 Relevant to Benefit ...... 32 6.4.4. Important Review Issue #4 Relevant to Benefit ...... 37 7. Risk and Risk Management ...... 39 7.1. Potential Risks or Safety Concerns Based on Nonclinical Data ...... 39 7.2. Potential Risks or Safety Concerns Based on Drug Class or Other Drug-Specific Factors ...... 39 7.3. Potential Safety Concerns Identified Through Postmarket Experience ...... 39 7.4. FDA Approach to the Safety Review ...... 40 7.5. Adequacy of the Clinical Safety Database ...... 40 7.6. Safety Findings and Safety Concerns Based on Review of the Clinical Safety Database ...... 41 7.6.1. Overall Adverse Event Summary ...... 41 7.6.2. Deaths ...... 42 ii Integrated Review Template, version date 2019/10/16

Reference ID: 4676324 NDA 209445 / S-002 Cefiderocol (Fetroja) 7.6.3. Serious Adverse Events...... 42 7.6.4. Dropouts and/or Discontinuations Due to Adverse Events ...... 47 7.6.5. Treatment-Emergent Adverse Events ...... 49 7.6.6. Laboratory Findings ...... 65 7.7. Review Issues Relevant to the Evaluation of Risk ...... 65 7.7.1. Important Risk Review Issue #1 ...... 65 7.7.2. Important Risk Review Issue #2 ...... 73 7.7.3. Important Risk Review Issue #3 ...... 75 7.7.4. Important Risk Review Issue #4 ...... 79 8. Therapeutic Individualization ...... 79 8.1. Intrinsic Factors ...... 79 8.2. Drug Interactions ...... 82 8.3. Pediatric Labeling/Plans for Pediatric Drug Development ...... 82 8.4. Pregnancy and Lactation ...... 84 9. Product Quality ...... 84 9.1. Device or Combination Product Considerations ...... 84 10. Human Subjects Protections/Clinical Site and Other GCP Inspections/Financial Disclosure ...... 85 11. Advisory Committee Summary ...... 85 III. Appendices ...... 85 12. Summary of Regulatory History ...... 85 13. Pharmacology Toxicology Assessments and Additional Information ...... 87 14. Clinical Pharmacology Assessment: Additional Information ...... 87 14.1. In Vitro Studies ...... 87 14.2. In Vivo Studies ...... 90 14.3. Population PK Analyses ...... 91 14.3.1. Review Summary ...... 91 14.3.2. Introduction ...... 92 14.3.3. Model Development ...... 93 14.3.4. Final Model ...... 95 14.3.5. Effect of Renal Function ...... 98 14.3.6. Comparison of Pharmacokinetics Between Patients With and Without Hemodialysis ...... 100 15. Trial Design: Additional Information and Assessment ...... 101 16. Efficacy Assessment Additional Information and Assessment ...... 110 17. Clinical Safety Assessment Additional Information and Assessment ...... 116 18. Mechanism of Action/Drug Resistance Additional Information and Assessment ...... 151 iii Integrated Review Template, version date 2019/10/16

Reference ID: 4676324 NDA 209445 / S-002 Cefiderocol (Fetroja) 19. Other Drug Development Considerations Additional Information ...... 179 20. Data Integrity-R Consults (OSI, Other Inspections) ...... 179 21. Labeling Summary of Considerations and Key Additional Information ...... 179 21.1. Prescribing Information ...... 179 22. Postmarketing Requirements and Commitments ...... 182 23. Financial Disclosure ...... 184 24. References ...... 185 25. Review Team Acknowledgements ...... 186

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Reference ID: 4676324 NDA 209445 / S-002 Cefiderocol (Fetroja) Table of Tables Table 1. Administrative Application Information ...... i Table 2. Benefit-Risk Framework ...... 7 Table 3. Clinical Trials Submitted in Support of Efficacy and/or Safety Determinationsa for Cefiderocol ...... 14 Table 4. Patient Experience Data Submitted or Considered ...... 15 Table 5. Summary of General Clinical Pharmacology and Pharmacokinetics ...... 16 Table 6. Overall Probability of Target Attainment (PTA) for 75%, 90%, and 100% fT > MIC in Plasma in Simulated Patients With Weighting for Distribution of CLcr in Phase 3 Studies ...... 20

Table 7. Overall PTA for 75%, 90%, and 100% fT > MICELF in Epithelial Lining Fluid (ELF) in Simulated Patients With Weighting for Distribution of CLcr in Phase 3 Studies ...... 20 Table 8. Baseline Demographic and Clinical Characteristics, ITT Population, APEKS-NP Trial ...... 23 Table 9. Baseline Microbiology Characteristics, ITT Population, APEKS-NP Trial ...... 25 Table 10. Medical History in ≥10% of Patients in Either Treatment Group, ITT Population, APEKS-NP Trial ...... 26 Table 11. Patient Disposition, ITT Population, APEKS-NP Trial ...... 27 Table 12. Length of Treatment in Days in the mITT Population, APEKS-NP Trial ...... 27 Table 13. All-Cause Mortality at Days 14 and 28 in the mITT Population, APEKS-NP Trial .....28 Table 14. Key Secondary Endpoints at Test of Cure in the mITT Population, APEKS-NP Trial 28 Table 15. Sensitivity Analysis of All-Cause Mortality at Day 14 After Start of Study Treatment Excluding Subjects With Potentially Effective Antibacterial Therapya ...... 30 Table 16. Key Endpoint Analyses Restricted to Subjects With Known Meropenem Susceptibility, APEKS-NP Trial ...... 31 Table 17. All-Cause Mortality by Baseline Pathogen, Restricted to Baseline Pathogens With Meropenem Susceptibility, APEKS-NP Trial ...... 31 Table 18. Clinical Outcome at Test of Cure by Baseline Pathogen, Restricted to Baseline Pathogens With Known Meropenem Susceptibility, APEKS-NP Trial ...... 32 Table 19. Summary of Clinical Cure and Microbiological Eradication Per Baseline Pathogen by Time Point -Modified Intention-to-Treat Population ...... 35 Table 20. FDA-Identified Breakpoints ...... 37 Table 21. Applicant’s Proposed Breakpoints ...... 37 Table 22. Revised FDA Identified Breakpoints ...... 38 Table 23. Duration of Exposure, Safety Population, APEKS-NP Trial ...... 41 Table 24. Overview of Treatment-Emergent Adverse Events, Safety Population, APEKS-NP Trial ...... 42 Table 25. Serious Adverse Events by System Organ Class and Preferred Term, Safety Population, APEKS-NP Trial ...... 44

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Reference ID: 4676324 NDA 209445 / S-002 Cefiderocol (Fetroja) Table 26. Serious Adverse Events by FDA MedDRA Query (Narrow), Safety Population, APEKS-NP Trial ...... 46 Table 27. TEAEs by System Organ Class Leading to Discontinuation, Safety Population, APEKS-NP Trial ...... 48 Table 28. Grouped Queries by Preferred Term, Occurring in at Least 4% of Patients in Cefiderocol Arm, Safety Population, APEKS-NP Trial ...... 50 Table 29. Subjects With Vital Sign Predefined Category Outliers at Postbaseline Safety Population ...... 56 Table 30. Maximum Postbaseline Decreases in Hemoglobin, APEKS-NP Trial ...... 57 Table 31. Laboratory Abnormalities for Electrolytes (CTCAE Version 5.0), Worsened Grade, Safety Population, APEKS-NP Trial ...... 58 Table 32. Hepatic TEAEs, Safety Population, APEKS-NP Trial ...... 60 Table 33. Maximum Increases in Liver Tests Postbaseline, Safety Population, APEKS-NP Trial (Unireview Table 59, Request 18) ...... 61 Table 34. Maximum Postbaseline Increase in PT-INR and aPTT, Safety Population, APEKS-NP Trial ...... 62 Table 35. FDA MedDRA Queriesa by System Organ Class Occurring at Higher Frequency in Treatment Arm Than in Comparator Arm ...... 64 Table 36. TEAEs Leading to Deaths by System Organ Class, Safety Population, APEKS-NP Trial ...... 67 Table 37. Deaths, Safety Population, APEKS-NP Trial ...... 68 Table 38. All-Cause Mortality at EOS by Meropenem Susceptibility and Baseline Pathogens, Safety Population ...... 70 Table 39. Mortality in Patients With Baseline A. baumannii Complex Species ...... 70 Table 40. Summary of All-Cause Mortality at EOS by Subgroups of Safety Population ...... 71 Table 41. All-Cause Mortality by Receipt of Blood Transfusion ...... 72 Table 42. Thrombotic and Embolic TEAEs, APEKS-NP Trial ...... 73 Table 43. Subjects With 4-Fold-Increase in Cefiderocol MIC During Treatment ...... 77 Table 44. Determination of Cefiderocol Daily Doses for Patients Receiving CRRT According to Effluent Flow Rate (QE) ...... 81

Table 45. Recommended Dose Regimens Adjusted Based on Effluent Flow Rates (QE) for Patients Receiving CRRT ...... 81 Table 46. Summary of In Vitro CRRT Experiments ...... 88 a Table 47. Cefiderocol CLCRRT During In Vitro CVVH as Determined by SC×Flow Rate ...... 89 a Table 48. Cefiderocol CLCRRT During In Vitro CVVHD as Determined by SA×Flow Rate ...... 89 Table 49. Cefiderocol Concentrations in Plasma and ELF and ELF/Plasma Concentration Ratios From Study R2117 ...... 91 Table 50. Specific Comments on Applicant’s Final Population PK model ...... 92 Table 51. Summary of Clinical Study Designs ...... 93

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Reference ID: 4676324 NDA 209445 / S-002 Cefiderocol (Fetroja) Table 52. Summary of Baseline Demographic Covariates for Analysis ...... 94 Table 53. Population Pharmacokinetic Parameter Estimates for the Final Model ...... 96 Table 54. Renal Function Groups and Adjusted Dose Regimens ...... 99 Table 55. Summary of Post hoc Estimates of Daily AUC at CrCL-Adjusted Dose Regimens by Study and Renal Function Group for Patients With Infection ...... 100 Table 56. Amount of Missing or Indeterminate Data in Key Endpoints in the mITT Population, APEKS-NP Trial ...... 110 Table 57. All-Cause Mortality at Days 14 and 28 in the mITT Population With “Worst-Case” Handling of Missing Data, APEKS-NP Trial ...... 111 Table 58. All-Cause Mortality at Days 14 and 28 in the mITT Population With Unknown Survival Status Treated as Death, APEKS-NP Trial ...... 112 Table 59. All-Cause Mortality by Baseline Pathogens With Known Meropenem Susceptibility in mITT Population, Treating Unknown Survival Status as Death, APEKS-NP Trial .....112 Table 60. Clinical Outcome at Different Time Points in the mITT Population, APEKS-NP Trial ...... 113 Table 61. Microbiological Outcome at Different Time Points in the mITT Population, APEKS- NP Trial ...... 114 Table 62. All-Cause Mortality at Day 14 in mITT Subgroups, APEKS-NP Trial ...... 114 Table 63. Liver Enzymes for Hy’s Law Screening for Patient 422010 ...... 119 Table 64. Liver Enzymes for Hy’s Law Screening for Patient 317001 ...... 120 Table 65. eGFR Shift Table, Safety Population ...... 121 Table 66. TEAEs by SOC and PT ...... 122 Table 67. TEAE incidence by Baseline Characteristics, Safety Population ...... 130 Table 68. SAE Incidence by Baseline Characteristics, Safety Population ...... 131 Table 69. List of Treatment-Emergent Adverse Events Leading to Discontinuation, Safety Population, APEKS-NP Trial ...... 133 Table 70. List of Deaths in Safety Population, APEKS-NP Trial ...... 137 Table 71. In Vitro Activity of Cefiderocol Against Gram-Negative Pathogens ...... 152 Table 72. In Vitro Activity of Cefiderocol Against Resistant Gram-Negative Pathogens ...... 152 Table 73. Percentage (%) of Cefiderocol Susceptible Isolates Against Cefepime-, Ceftazidime- Avibactam-, and Ceftolozane/Tazobactam-Nonsusceptible Isolates From SIDERO-WT ...... 153 Table 74. In Vitro Activity of Cefiderocol Against Molecularly Characterized Meropenem Nonsusceptible Isolates of Enterobacterales From Surveillance Studies ...... 156 Table 75. In Vitro Activity of Cefiderocol Against Molecularly Characterized Meropenem Nonsusceptible Isolates of Pseudomonas aeruginosa and Acinetobacter spp. From Surveillance Studies ...... 157 Table 76. Antibacterial Activity Against the Mutant Strains of P. aeruginosa PAO1 (EB-191-N) ...... 161

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Reference ID: 4676324 NDA 209445 / S-002 Cefiderocol (Fetroja) Table 77. Antibacterial Activity Against the Mutant Strains of P. aeruginosa PAO1 (EB-204-N) ...... 161 Table 78. Antibacterial Activity of Cefiderocol and Expression Level of Resistance Related Genes in Clinical Isolates of K. pneumoniae ...... 162 Table 79. Antibacterial Activity of Cefiderocol and Expression Level of Resistance Related Genes in Clinical Isolates of P. aeruginosa ...... 163 Table 80. Antibacterial Activity of Cefiderocol and Expression Level of Resistance Related Genes in Clinical Isolates of A. baumannii ...... 164 Table 81. In Vitro Activity of Cefiderocol and Comparators Against 72 Gram-Negative Clinical Isolates With Cefiderocol MICs of >4 mcg/mL Using CLSI Breakpoints ...... 166 Table 82. Summary of in Vivo Efficacy Studies Using Immunocompetent Rat Lung Infection Model ...... 173 Table 83. Summary of Clinical Cure and Microbiological Eradication at Test-of-Cure (TOC) Per Baseline Pathogen and Minimum Inhibitory Concentration Values in the Modified Intention-to-Treat Population ...... 176 Table 84. Mortality in Meropenem Resistant Isolates by Baseline Resistant Determinants ...... 178 Table 85. Summary of Key Labeling Modifications ...... 179 Table 86. Covered Clinical Studies: APEKS-NP Trial ...... 184 Table 87. Reviewers of Interdisciplinary Assessment ...... 186 Table 88. Additional Reviewers of Application ...... 186 Table 89. Signatures of Reviewers ...... 186

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Reference ID: 4676324 NDA 209445 / S-002 Cefiderocol (Fetroja) Table of Figures Figure 1. 14-Day ACM Among Subjects With Acinetobacter Infections at Baseline by MIC to Meropenem, APEKS-NP ...... 33 Figure 2. Observed Plasma Cefiderocol Concentration Profiles for Patients With or Without Hemodialysis in CREDIBLE-CR and APEKS-NP Studies ...... 80 Figure 3. Predicted Plasma Concentrations in Patients Receiving CRRT at the Recommended QE-Based Dose Regimens and Prediction Interval of Plasma Concentrations for Patients Not Receiving CRRT at 2 g q8h ...... 82 Figure 4. Goodness-of-Fit Plots for Final Covariate Model ...... 96 Figure 5. pcVPC Plots for Final Covariate Model ...... 97 Figure 6. Box Plots for Bayesian-Estimated CL by Study and Renal Function Group ...... 99 Figure 7. Observed Plasma Cefiderocol Concentration Profiles for Patients With or Without Hemodialysis in CREDIBLE-CR Trial ...... 101 Figure 8. Kaplan-Meier Survival Curves in the mITT Population, APEKS-NP Trial ...... 113 Figure 9. Observed Result for Hepcidin (nmol/L) ...... 117 Figure 10. Observed Result for Total Iron Binding Capacity (TIBC) (mcmol/L) ...... 117 Figure 11. Observed Result for Iron (mcmol/L) ...... 117 Figure 12. Observed Result for Transferrin Saturation (%) ...... 118 Figure 13. Observed Result for Hematocrit ...... 118 Figure 14. Observed Result for Hemoglobin (HGB) (g/L)...... 118 Figure 15. Hy’s Law Plot ...... 120 Figure 16. Relationship Between the Expression Level of MexA and MIC of Aztreonam (A) or Cefiderocol (B) Against P. aeruginosa ...... 165 Figure 17. Efficacy of 24 Hours of a Cefiderocol Human-Simulated Regimen (2 g q8h, 3-Hour Infusion) and a Ceftazidime Human-Simulated Regimen (2 g q8h, 2-Hour Infusion) Against Ceftazidime-Susceptible (A) and Ceftazidime-Resistant (B) S. maltophilia in Neutropenic Murine Thigh Infection Model ...... 169 Figure 18. Efficacy of 24 Hours of a Cefiderocol Human-Simulated Regimen (HSR) (2 g q8h, 3- Hour Infusion) Against E.coli and K. pneumoniae (A), A. baumannii (B), and P. aeruginosa (C) in Standard and Iron Overloaded Murine Thigh Infection Models ...... 170 Figure 19. Bacterial Reduction Against Each Isolate of Enterobacteriaceae in Murine Thigh Infection Models Under Humanized PK of Cefiderocol ...... 171 Figure 20. Bacterial Reduction Against Each Isolate of P. aeruginosa in Murine Thigh Infection Models Under Humanized PK of Cefiderocol ...... 171 Figure 21. Bacterial Reduction Against Each Isolate of A. baumannii in Murine Thigh Infection Models Under Humanized PK of Cefiderocol ...... 172

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Reference ID: 4676324 NDA 209445 / S-002 Cefiderocol (Fetroja)

Glossary

ABG arterial blood gas ACC Ambler class C ACM all-cause mortality ACT AmpC type ADC Acinetobacter-derived cephalosporinase AE adverse event AKI acute kidney injury ALB albumin ALP alkaline phosphatase ALT alanine aminotransferase APACHE Acute Physiology and Chronic Health Evaluation APEKS-NP Acinetobacter baumannii, Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumoniae, and Stenotrophomonas maltophilia in Nosocomial Pneumonia aPTT activated partial thromboplastin time AR adverse reaction ARDS acute respiratory distress syndrome ARLG Antimicrobial Resistance Leadership Group AST aspartate aminotransferase AUC area under the concentration-time curve AUP acute uncomplicated pyelonephritis AZT aztreonam BAL bronchoalveolar lavage BILI bilirubin BSI bloodstream infection CAMHB Cation Adjusted Mueller Hinton Broth Cdialysate concentration in dialysate CHF congestive heart failure CI confidence interval CKD chronic kidney disease CLcr creatinine clearance CLCRRT clearance by ultrafiltration or dialysis of continuous renal replacement therapy CLCVVH clearance by continuous venovenous hemofiltration CLCVVHD clearance by continuous venovenous hemodialysis CLnonrenal nonrenal clearance CLSI Clinical and Laboratory Standards Institute CMC chemistry, manufacturing, and controls CMH Cochran-Mantel-Haenszel CMY cephalosporinase COPD chronic obstructive pulmonary disease COVID-19 coronavirus disease 2019 Cpost concentration from a postfilter sampling port Cpre concentration from an undiluted prefilter sampling port 1 Integrated Review Template, version date 2019/10/16

Reference ID: 4676324 NDA 209445 / S-002 Cefiderocol (Fetroja) CREDIBLE-CR A Multicenter, Randomized, Open-label Clinical Study of S-649266 or Best Available Therapy for the Treatment of Severe Infections Caused by Carbapenem-Resistant Gram-Negative Pathogens CRRT continuous renal replacement therapy CT computed tomography CTX-M cefotaximase Cuf concentration in ultrafiltrate CVA cerebrovascular accident CVVDF continuous venovenous diafiltration CVVH continuous venovenous hemofiltration CVVHD continuous venovenous hemodialysis CVVHDF continuous venovenous hemodiafiltration DAI Division of Anti-Infectives DHA Dhahran Hospital DM diabetes mellitus DSMB Data Safety Monitoring Board EA early assessment ECMO extracorporeal membrane oxygenation eGFR estimated glomerular filtration rate ELF epithelial lining fluid EOS end of study EOT end of treatment ESBL extended-spectrum β-lactamase ESRD end-stage renal disease FDA Food and Drug Administration FMQ FDA Medical Dictionary for Regulatory Activities Query FOX cefoxitin FU follow-up fu free fraction of drug in plasma GCP good clinical practice GES Guiana extended-spectrum β-lactamase GFR glomerular filtration rate GGT gamma-glutamyl transferase GI gastrointestinal GIM German imipenemase HABP hospital-acquired bacterial pneumonia HAP hospital-acquired pneumonia HCABP healthcare-associated bacterial pneumonia HCAP healthcare-associated pneumonia HTN hypertension ID-CAMHB Iron Depleted Cation Adjusted Mueller Hinton Broth IMP imipenemase metallo-β-lactamase IND investigational new drug INR international normalized ratio IPM imipenem iPSP initial pediatric study plan

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Reference ID: 4676324 NDA 209445 / S-002 Cefiderocol (Fetroja) ITT intention-to-treat IV intravenous KPC Klebsiella pneumoniae carbapenemase LFT liver function test LOE lack of efficacy Mex multidrug efflux pump MDR multidrug-resistant MI myocardial infarction MIC minimum inhibitory concentration MIC90 minimum inhibitory concentration required to inhibit 90% of tested isolates MIR Miriam Hospital mITT modified intention-to-treat MODS multiple organ dysfunction syndrome MOX moxalactam MRSA methicillin-resistant Staphylococcus aureus NDA new drug application NDM New Delhi metallo-β-lactamase NI noninferiority NP nosocomial pneumonia OBJ objective function value Opr outer membrane porin OXA oxacillinase pcVPC prediction-corrected visual predictive check PD pharmacodynamics PDC Pseudomonas-derived cephalosporinase PDUFA Prescription Drug User Fee Act PE pulmonary embolism PER Pseudomonas extended resistance PK pharmacokinetics PPK population pharmacokinetics PSP pediatric study plan PMR postmarketing requirement PT preferred term Qb blood flow rate Qd dialysate flow rate QE effluent flow rate Qrep prefilter replacement fluid rate Quf ultrafiltrate/replacement fluid flow rate SA saturation coefficient SAE serious adverse event SC sieving coefficient SD standard deviation SHV sulfhydryl variable sNDA supplemental new drug application SOC system organ class

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Reference ID: 4676324 NDA 209445 / S-002 Cefiderocol (Fetroja) SPM São Paulo metallo-β-lactamase TEAE treatment-emergent adverse event TEM temoneira TOC test-of-cure ULN upper limit of normal UTI urinary tract infection VABP ventilator-associated bacterial pneumonia VAP ventilator-associated pneumonia VIM Verona integron-encoded metallo-β-lactamase WBC white blood cell XDR extensively drug-resistant

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Reference ID: 4676324 NDA 209445 / S-002 Cefiderocol (Fetroja)

I. Executive Summary

1. Summary of Regulatory Action

Cefiderocol (FETROJA™) is approved for treatment of adults with complicated urinary tract infections (cUTI). This supplemental NDA (sNDA) proposes to add a second indication, treatment of hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (HABP/VABP) based upon APEKS-NP (NCT02321800), a double-blind, active- controlled, randomized, noninferiority trial conducted to compare Fetroja to meropenem. This sNDA was reviewed by a multidisciplinary review team. Each discipline has recommended approval of the sNDA, and I, the signatory authority for this application, concur with the recommendations. In support of this indication, the APEKS-NP clinical trial met its primary endpoint of noninferiority of cefiderocol to meropenem for day 14 all-cause mortality (ACM) in the modified intent-to treat (mITT) population: day 14 ACM was 12.4% in the cefiderocol and 11.6% in the meropenem group for a treatment difference of 0.8 (95% confidence intervals, -6.6, 8.2). The secondary endpoints of day 28 all-cause mortality and clinical outcomes supported the finding of noninferiority (see benefit-risk assessment, below). The Statistical Review team concurs that appropriate statistical inference testing was conducted, and this single adequate and well-controlled trial provides substantial evidence of effectiveness of cefiderocol for the treatment of HABP/VABP due to the designated susceptible bacteria. Additional supportive information was provided from in vitro studies and animals models of infection. The safety profile of cefiderocol was generally similar to meropenem in the APEKS-NP trial. The study population consisted of severely ill patients, and deaths occurred in approximately one-quarter of patients and serious adverse events in approximately one-third of patients in both treatment groups (see benefit-risk summary, and review Sections 7.6-7.7). The clinical review team recommends providing information on the adverse reactions (ARs) observed in the APEKS-NP trial in section 6 of labeling (Adverse Reactions) and routine postmarketing surveillance. Notable labeling changes include dosing recommendations for patients undergoing continuous renal replacement therapy (CRRT; discussed in Sections 8.1, 14.1, and 11 of this review). The current labeling contains a warning in section 5.1 describing an increase in all-cause mortality based upon observations in a randomized, open-label trial (CREDIBLE-CR) in patients with cUTI, nosocomial pneumonia, bloodstream infections, or sepsis due to carbapenem-resistant gram-negative bacteria. The cause of the increased mortality was not established, but some deaths were attributed to treatment failure or underlying conditions (Division of Anti-Infectives 2019). The current trial in HABP/VABP with carbapenem-susceptible organisms provides some reassuring safety data; however, the clinical review team recommends retaining the warning from the CREDIBLE-CR trial as the safety concern remains regarding the risk of mortality in patients with carbapenem-resistant infections. The data from the APEKS-NP trial supports the safety and effectiveness of cefiderocol for the treatment of HABP/VABP and mutually supports the previous finding of safety and

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Reference ID: 4676324 NDA 209445 / S-002 Cefiderocol (Fetroja) effectiveness for the treatment of cUTI. In both trials, the 10% noninferiority margin recommended for a standard indication was met; therefore, the limited use statement in the product labeling is recommended to be removed. The overall benefit-risk is favorable as summarized in the Benefit-Risk Assessment below. For detailed information supporting the basis for this approval, please refer to the detailed reviews included in this Interdisciplinary Assessment document and the separate Product Quality Review.

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2. Benefit-Risk Assessment

Table 2. Benefit-Risk Framework Dimension Evidence and Uncertainties Conclusions and Reasons Analysis of • Hospital-acquired and ventilator-associated bacterial pneumonia HABP and VABP are serious infections that cause Condition (HABP/VABP) are acute infections of the lung parenchyma that significant morbidity and mortality in hospitalized occur in hospitalized patients. patients. • HABP is generally defined as occurring 48 hours or more after hospital admission and is not associated initially with mechanical ventilation. • Ventilated HABP (vHABP) is a subset of HABP in which patients with HABP require mechanical ventilation as part of their treatment. VABP is generally defined as occurring 48 hours or more after endotracheal intubation. • Both conditions are associated with acute respiratory symptoms and the presence of new or progressive infiltrates on chest radiograph. • The microbiology of HABP and VABP include gram-positive bacteria, such as S. aureus, and gram-negative bacteria, such as P. aeruginosa, Acinetobacter spp., and Enterobacterales. Antibacterial resistance is commonly observed in bacterial isolates that cause HABP and VABP. • Mortality among patients with HABP and VABP has been reported to be 20 to 50% (Alp et al. 2004). Current • The initial treatment of HABP/VABP is empiric as culture results There are several antibacterial drugs approved to treat Treatment are typically not initially available, but usually includes HABP/VABP, but antimicrobial resistance and patient Options intravenous (IV) antibacterial drugs that cover S. aureus and P. factors may limit their use. aeruginosa. • The choice of antibacterial drugs depends on the local epidemiology and patient risk factors for resistant organisms. The antibacterial drug regimen is usually tailored after culture results are available. • FDA-approved antibacterial drugs with gram-negative coverage that are used for the treatment of HABP/VABP include β- lactam/β-lactam inhibitor combinations (ceftolozane/tazobactam, ceftazidime/avibactam, piperacillin-tazobactam), certain cephalosporins, fluoroquinolones, monobactams, aminoglycosides, and carbapenems.

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Dimension Evidence and Uncertainties Conclusions and Reasons Benefit • The efficacy of cefiderocol in treatment of HABP/VABP was The submitted evidence showed noninferiority of evaluated in a randomized clinical trial (APEKS-NP) that cefiderocol to meropenem for ACM at day 14. A key compared cefiderocol 2 grams IV every 8 hours with meropenem secondary endpoint of microbiological cure did not 2 grams IV every 8 hours. Linezolid was given to patients in both demonstrate statistical significance, and other treatment groups for treatment of possible concomitant infection endpoints (day 28 and clinical cure) were considered with gram-positive organisms. Of 300 patients, 148 and 152 exploratory. Day 28 ACM rates were similar across were randomized to receive either cefiderocol or meropenem, treatment groups and clinical cure rates slightly respectively. There were no significant issues with trial design, disfavored cefiderocol. conduct, or analysis. • The primary endpoint was all-cause mortality (ACM) at day 14. The analysis of key endpoints when restricting to Secondary endpoints included ACM at day 28, clinical and patients with meropenem susceptible pathogens (MIC microbiological outcome at the test-of-cure visit (TOC), which ≤8 mcg/mL based on 2 g 3hour infusion) did not occurred about 7 days after the end of treatment. The mortality demonstrate significant differences between the and clinical outcome endpoints are measures of clinical benefit treatment groups. (how a patients survives, feels, and functions). • ACM at day 14 and day 28 was 12.4% and 22.1% in the The mortality and clinical cure endpoints were relatively cefiderocol and 12.2% and 21.1% in the meropenem group similar in the overall subset of patients with A. respectively in the modified intention-to-treat (mITT) population. baumannii complex (N=51) and a few subgroups with The results of ACM at day 14 met the threshold for noninferiority. increasing MIC to meropenem trended favorably for • Clinical cure at TOC was 64.8% in the cefiderocol and 66.7% in cefiderocol. As this information reflects that cefiderocol the meropenem group. Microbiological cure at TOC was 47.6% likely has efficacy in treatment of patients with A. in the cefiderocol and 48% in the meropenem group. baumannii complex HABP/VABP, A. baumannii • The results are similar between treatment groups across various complex was included in the indication and List 1 in patient subgroups and robust to sensitivity analyses. labeling. • To ensure that the efficacy results were not largely driven by meropenem-nonsusceptibility; i.e., by the possibility that a The table in the Clinical Studies section of the labeling significant proportion of subjects in the meropenem arm were will present the comparative results from patients with unlikely to benefit from meropenem, the key efficacy analyses meropenem-susceptible A.baumannii complex at were repeated by restricting them to patients where the isolate baseline and additional information on outcomes in was susceptible to meropenem. The results corroborated the patients with HABP/VABP due to A. baumannii complex original results from the full mITT population. will be described in this section so that the healthcare • As only 59% of the mITT population had subjects known to be provider can take this information into consideration susceptible to meropenem, the differences in efficacy in certain while making treatment decisions. subgroups based on baseline pathogen were difficult to discern. • At baseline, 51 subjects were infected with A. baumannii complex however only 17 (33%) had meropenem-susceptible isolates . Of these 17 isolates, there were (<10) isolates in either treatment group. Generally, for inclusion of an organism in the indication, clinical data in the test arm on at least 10 isolates is 8 Integrated Review Template, version date 2019/10/16

Reference ID: 4676324 NDA 209445 / S-002 Cefiderocol (Fetroja)

Dimension Evidence and Uncertainties Conclusions and Reasons expected. In these 51 patients, clinical cure rates, ACM at day 14 and 28 slightly disfavored cefiderocol, and the mortality imbalance in the CREDIBLE-CR trial in the subgroup of patients with A. baumannii also raised concerns about including this organism in the indication. • When all Acinetobacter isolates (N=53) were included in efficacy analysis, the ACM mortality at day 14 and 28 were similar between treatment groups. Moreover, in the subgroups of patients with MIC to meropenem ranging from >16 to >64 mcg/mL, day 14 ACM may have favored the cefiderocol group.

Risk and • The safety database included 148 patients of which 97 received There are limitations to the safety and causality Risk the proposed dose and duration of cefiderocol (7-14 days), 33 assessment given the relative small size of the safety Management received >14 days, and 18 received <7 days of cefiderocol. database and the complexity of patients’ underlying Relative to recent HABP/VABP studies, this is a small safety comorbidities. database. Patient characteristics were adequately represented in terms of gender and age. Patients from the United States The benefits and risk of cefiderocol have been were underrepresented (4%) but significant regional differences communicated in labeling. Monitoring for TEAEs of in HABP/VABP trials are not anticipated. Approximately 50 special interest will continue in the postmarketing percent were receiving mechanical ventilation at enrollment phase. No specific risk mitigation strategies are needed (VABP/vHABP). at this time. • The following adverse reactions (ARs) occurred in at least 4% of cefiderocol-treated patients: elevated liver tests, anemia, hypokalemia, diarrhea, hypomagnesemia, and atrial fibrillation. • Treatment-emergent adverse events (TEAEs) leading to death occurred in 26.4% [39/148] in the cefiderocol group and 23.3% [35/150] in the meropenem group (a risk difference of 3.1%). • While some deaths appeared to be related to lack of efficacy or an adverse reaction (AR), the majority in both treatment groups appeared to be related to underlying medical conditions or concurrent illness in a critically ill population. • A higher number of arterial thromboembolic events (e.g., myocardial infarction, intestinal infarction) were reported and proposed as ARs in labeling. • Seizures, Clostridioides difficile-associated diarrhea, and hypersensitivity reactions were reported and are already in current labeling.

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Reference ID: 4676324 NDA 209445 / S-002 Cefiderocol (Fetroja) Conclusions Regarding Benefit-Risk In this sNDA, the Applicant is seeking an indication for the treatment of HABP/VABP. Bacterial infections of the lung parenchyma are serious, frequently life threatening infections that are often associated with antibacterial drug resistance, particularly when acquired in a healthcare setting. While there are multiple antibacterial drugs currently approved to treat HABP/VABP, antimicrobial resistance continues to evolve which may limit the utility of the current armamentarium. Cefiderocol is a modified cephalosporin that utilizes a siderophore-based entry mechanism into gram-negative bacterial cells; therefore, it may offer a treatment option for some patients with HABP/VABP. The submitted evidence met the statutory standard for effectiveness. The APEKS-NP trial achieved the primary objective demonstrating that cefiderocol is noninferior to meropenem in the treatment of patients with HABP/VABP with respect to the primary endpoint of ACM at day 14 in the mITT population (cefiderocol 12.4%, meropenem 11.6% [difference 0.8%; 95% CI: - 6.6 to 8.2]). This conclusion was supported by the secondary endpoint assessments of ACM at day 28 (cefiderocol 21.0%, meropenem 20.5% [difference 0.5%; 95% CI: - 8.7 to 9.8]), and clinical cure, which assessed the resolution of signs and symptoms of disease. The favorable clinical response at the TOC visit in the mITT population was 64.8% and 66.7%, in the cefiderocol and meropenem groups, respectively (difference – 2.0%; 95% CI: - 12.5 to 8.5). Various sensitivity analyses of the primary endpoint produced similar conclusions as the primary analysis when accounting for potentially confounding factors, such as prior and concomitant antibacterial therapy as well as missing data (Sections 6.4.1 and 16). Subgroup analyses by subject demographics and disease characteristics were consistent with the primary results. Certain subgroup analyses of the micro-ITT population were limited by small sample sizes, such as analyses by baseline pathogen. Noninferiority was preserved in the subgroup of patients who strictly met the criteria for study inclusion as described by the FDA guidance Hospital-Acquired Bacterial Pneumonia and Ventilator-Associated Bacterial Pneumonia: Developing Drugs for Treatment (June 2020). The main issue affecting interpretability were the criteria for meropenem susceptibility when utilizing a high dose, extended duration of infusion dosing regimen (Section 6.4.2). With a sensitivity analysis restricted to patients with meropenem susceptible pathogens, as defined by MIC ≤8 mcg/mL, there were no significant differences between the treatment groups (Section 6.4.2). The safety database from the APEKS-NP trial included 148 patients of which 97 received the proposed dose and duration of cefiderocol. Patient demographic characteristics were balanced, and approximately 50% were mechanically ventilated at enrollment (VABP/ventilated HABP). Overall, safety profiles were similar between cefiderocol and meropenem. The most common TEAEs (greater than or equal to 4% incidence) experienced by patients in this trial were the following: elevated liver tests, anemia, hypokalemia, diarrhea, hypomagnesemia, and atrial fibrillation. TEAEs leading to death occurred in 26.4% [39/148] in the cefiderocol group and 23.3% [35/150] in the meropenem group (a risk difference of 3.1%). The majority of deaths in both treatment groups appeared to be related to underlying medical conditions or concurrent illness in a critically ill population. The reported adverse events in the HABP/VABP patient population were generally consistent with the known safety profile of cefiderocol observed in the trial for cUTI. Most adverse reactions (ARs), such as seizures, Clostridioides difficile-associated diarrhea, and hypersensitivity reactions are

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(b) (4) already described in the current labeling. ARs added to the labeling include thromboembolic events (e.g., myocardial (b) (4) infarction,), and electrolyte abnormalities. There are limitations to the safety and causality assessment given the relative small size of the safety database and the complexity of patients’ underlying comorbidities. The overall benefit-risk assessment of cefiderocol for the treatment of HABP/VABP is favorable. A descriptive study (CREDIBLE- CR) raises concerns about the potential for a decrement in efficacy with cefiderocol in patients with HABP/VABP and bacteremia, particularly those caused by certain carbapenem-resistant, lactose non-fermenting Gram-negative bacteria such as P. aeruginosa, A. baumannii and S. maltophilia. The primary analysis population in the APEKS-NP trial was carbapenem-susceptible organisms due to the selection of meropenem as the comparator. The point estimate of 14- and 28-day mortality was lower for patients with P. aeruginosa at baseline who were treated with cefiderocol (Section 6.4.2, Table 17). The majority of subjects with A. baumannii at baseline were not included in the primary analysis due to carbapenem-resistance; however, an examination of patient outcomes regardless of susceptibility of the baseline pathogen across study endpoints and timepoints did not raise safety concerns (Sections 6.4.3, and 7.1). No deaths occured through day 28 in the small subgroup of patients who were treated with cefiderocol (n=5) with A. baumannii at baseline with a meropenem MIC >64 mcg/ml. While the data from APEKS-NP are reassuring, the current warning in labeling will be retained since the findings from CREDIBLE-CR trial are not fully explained, and APEKS-NP was not designed to assess carbapenem-resistant pathogens.

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II. Interdisciplinary Assessment

3. Introduction Cefiderocol (Fetroja) is a structurally modified cephalosporin antibacterial drug that utilizes a siderophore-based mechanism for bacterial cell entry. Cefiderocol was approved on November 14, 2019, for the treatment of complicated urinary tract infections (cUTI) including pyelonephritis due to susceptible gram-negative bacteria in adults with limited to no alternative treatment options. The proposed indication is for the treatment of hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (HABP/VABP) caused by carbapenem-susceptible gram-negative bacteria in adults with limited or no alternative treatment options. The proposed dosing regimen is 2 grams by intravenous (IV) administration every 8 hours (with dosing adjustment for renal impairment) for 7 to 14 days. In hospitalized patients with pneumonia, gram-negative organisms can account for >60% of isolated bacteria, with one of the most frequently isolated pathogens being Pseudomonas aeruginosa. Other common gram-negative pathogens isolated in patients with HABP and VABP are Escherichia coli, Klebsiella pneumoniae, Enterobacter spp. and Acinetobacter spp. Currently available treatment options for HABP/VABP due to gram-negative bacteria include carbapenems, β-lactam/β-lactamase inhibitor combinations, cephalosporins, fluoroquinolones, and aminoglycosides. The initial empiric treatment is guided by the patient’s risk factors, local epidemiology, and antibacterial susceptibility patterns. Empiric treatment usually includes coverage for Staphylococcus aureus, P. aeruginosa, and other gram-negative bacilli. Definitive treatment follows based on the diagnostic workup and the clinical response to empiric treatment. Cefiderocol was granted both fast track and Qualified Infectious Disease Product designation on August 18, 2015, for this indication. The supplemental new drug application (sNDA) contains results of the APEKS-NP trial (Acinetobacter baumannii, Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumoniae, and Stenotrophomonas maltophilia in Nosocomial Pneumonia, ClinicalTrials.gov ID 1615R2132), a phase 3, multicenter, randomized, parallel-group, double- blind, active-controlled noninferiority (NI) trial comparing cefiderocol to meropenem for the treatment of HABP/VABP/HCABP. Linezolid was administered to subjects in both study arms to provide coverage for methicillin-resistant S. aureus. The primary endpoint of the study was all-cause mortality (ACM) at day 14 in the modified intention-to-treat (mITT) population. The following review issues were identified and discussed in Sections 6.4 and 7.7. • Confounding of treatment effect by prior and concomitant antibacterial drugs • Inclusion of Acinetobacter, S. maltophilia and Burkholderia cepacia in List 1 • Sensitivity analysis excluding patients with meropenem-nonsusceptible pathogens • Revisit breakpoints established by FDA for Enterobacteriaceae and P. aeruginosa and establish breakpoints for A. baumannii complex • Mortality analysis • Thromboembolic treatment-emergent adverse event (TEAE) analysis

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Reference ID: 4676324 NDA 209445 / S-002 Cefiderocol (Fetroja) • Potential for resistance development (increases in minimum inhibitory concentration [MIC] on therapy) 3.1. Approach to the Review The original new drug application (NDA) submitted for the approval of cUTI, including pyelonephritis included six clinical pharmacology studies, a completed phase 2 cUTI trial, and a study summary and datasets from the CREDIBLE-CR trial (A Multicenter, Randomized, Open- label Clinical Study of S-649266 or Best Available Therapy for the Treatment of Severe Infections Caused by Carbapenem-Resistant Gram-Negative Pathogens, ClinicalTrials.gov ID 1424R2131). The CREDIBLE-CR trial results were analyzed during the review of the original NDA; the clinical study report, which was previously unavailable, has been submitted with the sNDA in response to a postmarketing requirement. In this sNDA review, the single trial in HABP/VABP (APEKS-NP) is reviewed in support of the efficacy and safety of cefiderocol in patients with HABP/VABP. Although the CREDIBLE-CR trial enrolled patients with this indication, the trial was primarily conducted to study carbapenem-resistant pathogens and had distinct features which precluded pooling of efficacy or safety results. At the pre-NDA stage, it was agreed with the Applicant that results of the APEKS-NP trial and the HABP/VABP subgroup of the CREDIBLE-CR trial would be analyzed separately. Table 3 provides an overview of the clinical trials important to the review of cefiderocol efficacy and safety. CREDIBLE-CR trial information has been included here as information from patients receiving continuous renal replacement therapies (CRRTs) in this trial informed CRRT dosing in the labeling. The review team’s approach included identifying key benefit and risk issues at the pre-NDA meetings. The key benefit and risk issues are addressed in the Sections 6.4 and 7.7, respectively. Several information requests were also sent to the Applicant to supplement or clarify information contained in the sNDA.

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Table 3. Clinical Trials Submitted in Support of Efficacy and/or Safety Determinationsa for Cefiderocol Number of Number of Regimen (Number. Primary and Key Subjects Centers and Trial Identifier Trial Population Trial Design Treated), Duration Secondary Endpoints Randomizedb Countries 1615R2132 Adults with NP Phase 3, MC, R, Drug: Cefiderocol Primary: Planned: 300 Centers: 104 APEKS-NP (HABP/VABP/HCABP) DB, AC, PG Dose: 2 g IV q8h All-cause mortality at day 14 (150 in each NCT03032380 caused by a susceptible Number treated: 148 in mITT population treatment group) Countries: 17 gram-negative Duration: 7-21 d Secondary: pathogen who required Microbiological and clinical Actual: 300 hospitalization outcomes at EA, EOT, TOC, subjects (148 in FU, all-cause mortality at cefiderocol day 28 and EOS group, 152 in meropenem group) 1424R2131 Adults with NP, Phase 3, MC, R, Drug: Cefiderocol Primary: Planned: 152 Centers: 95 CREDIBLE-CR BSI/sepsis, or cUTI OL, AC, PG Dose: 2 g IV q8h Clinical outcome at TOC in Actual: 150 NCT02714595 caused by a Number treated: 101 patients with NP, Countries: 16 carbapenem-resistant Duration: 7-21 d BSI/sepsis; microbiological gram-negative outcome at TOC in patients pathogen with cUTI Secondary: All-cause mortality at day 14, 28 for NP, BSI/sepsis; clinical and microbiological outcome at EA, EOT Source: Reviewer a Includes all submitted clinical trials, even if Not Reviewed in-depth, except for phase 1 and pharmacokinetic studies. b If no randomization, then replace with “Actual Enrolled” Abbreviations: AC, active-controlled; BSI, bloodstream infection; cUTI, complicated urinary tract infections; DB, double-blind; EA, early assessment; EOS, end of study; EOT, end of treatment; FU, follow-up; HABP, healthcare-acquired bacterial pneumonia; HCABP, healthcare-associated bacterial pneumonia; IV, intravenous; MC, multicenter; mITT, modified intention-to-treat; NP, nosocomial pneumonia; OL, open-label; PG, parallel group; q8h, every 8 hours; R, randomized; TOC, test-of-cure; VABP, ventilator-associated bacterial pneumonia

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4. Patient Experience Data

Table 4. Patient Experience Data Submitted or Considered Data Submitted in the Application Check if Section Where Submitted Type of Data Discussed, if Applicable Clinical outcome assessment data submitted in the application ☐ Patient-reported outcome 6.3 ☐ Observer-reported outcome ☒ Clinician-reported outcome Performance outcome ☐ Other patient experience data submitted in the application Patient-focused drug development meeting summary ☐ ☐ Qualitative studies (e.g., individual patient/caregiver interviews, focus group interviews, expert interviews, Delphi Panel) ☐ Observational survey studies Natural history studies ☐ ☐ Patient preference studies Other: (please specify) ☐ If no patient experience data were submitted by Applicant, indicate here. ☐ Data Considered in the Assessment (but Not Submitted by Applicant) Check if Section Where Considered Type of Data Discussed, if Applicable ☐ Perspectives shared at patient stakeholder meeting Patient-focused drug development meeting summary report ☐ Other stakeholder meeting summary report ☐ Observational survey studies ☐ Other: (please specify) ☐

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Reference ID: 4676324 NDA 209445 / S-002 Cefiderocol (Fetroja) 5. Pharmacologic Activity, Pharmacokinetics, and Clinical Pharmacology

Table 5. Summary of General Clinical Pharmacology and Pharmacokinetics Characteristic Drug Information Pharmacologic Activity Established Fetroja is a cephalosporin antibacterial drug product. pharmacologic class Mechanism of action Fetroja is a cephalosporin antibacterial with activity against gram-negative aerobic bacteria. Cefiderocol functions as a siderophore and binds to extracellular free (ferric) iron. In addition to passive diffusion via porin channels, cefiderocol is actively transported across the outer cell membrane of bacteria into the periplasmic space using the bacterial siderophore iron uptake mechanism. Cefiderocol exerts bactericidal action by inhibiting cell wall biosynthesis through binding to penicillin-binding proteins (PBPs). Active moieties Cefiderocol QT prolongation At doses 1 and 2 times the maximum recommended dosage, Fetroja does not prolong the QT interval to any clinically relevant extent. General Information Bioanalysis Validated HPLC/MS/MS methods were used to determine the concentrations of cefiderocol in plasma and urine. Healthy subjects versus No clinically meaningful differences in cefiderocol PK were observed between patients patients with infection and healthy subjects. Drug exposure at steady HABP/VABP Healthy state following the cUTI Patientsa Patientsb Volunteersc therapeutic dosing PK Parameters N=238 N=146 N=43 d regimen (or single dose, Cmax (mg/L) 114 (41.5) 99.7 (46.9) 89.7 (21) d if more relevant for the AUC0-24 hrs (mg·hr/L) 1062 (40.3) 1560 (53.0) 1158 (17203) drug) a After multiple (every 8 hours) Fetroja 2-gram doses infused over 1 hour (1/3 of the recommended infusion duration) in cUTI patients with CLcr 60 mL/min or greater b After multiple (every 8 hours) Fetroja 2-gram doses infused over 3 hours or adjusted based on renal function c After a single Fetroja 2-gram dose was infused over 3 hours in healthy volunteers with CLcr 60 mL/min or greater d Mean (%CV) Abbreviations: AUC, area under the curve; CLcr, creatinine clearance; Cmax, maximum plasma concentration; cUTI, complicated urinary tract infection; CV, coefficient of variation; HABP, hospital-acquired bacterial pneumonia; VABP, ventilator-associated bacterial pneumonia Range of effective Cefiderocol PK/PD target was determined to be 75% TCf > MIC/τ for 1-log10 dose(s) or exposure bacterial reduction based on a neutropenic murine thigh infection model. Compared to a 1-hour infusion, a 3-hour infusion increased the percent time of dosing interval that unbound plasma concentrations of cefiderocol exceed the MIC. Maximally tolerated dose An MTD was not determined. The highest evaluated dose in humans was (MTD) or exposure 4000 mg single dose (in a TQT trial). Dose proportionality The Cmax and AUC of cefiderocol increased in a dose-proportional manner within the dose range from 100 to 4000 mg. Accumulation After administration of 2 g doses of cefiderocol q8h, no accumulation was observed for Cmax or AUC. Time to achieve steady- Steady state was attained within 1 day after the start of multiple dose state administration. Bridge between to-be The to-be-marketed g/vial solution for infusion formulation was used in the marketed and clinical pivotal clinical trials. trial formulations

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Reference ID: 4676324 NDA 209445 / S-002 Cefiderocol (Fetroja)

Characteristic Drug Information Absorption Bioavailability Not relevant Tmax Not relevant Food effect (fed/fasted) Not relevant geometric least square mean and 90% CI Distribution Volume of distribution Volume of distribution during the terminal phase (Vz) of cefiderocol was 18.0 L (18.1%) [geometric mean (%CV)]. Plasma protein binding 58% Lung distribution Following a Fetroja 2-gram dose at steady state (or renal function equivalent dose) in patients with pneumonia requiring mechanical ventilation with a 3- hour infusion, the cefiderocol concentrations in epithelial lining fluid (ELF) ranged 3.1 to 20.7 mg/L and 7.2 to 15.9 mg/L at the end of infusion and at 2 hours after the end of infusion, respectively. Drug as substrate of Cefiderocol was not a substrate of OAT1, OAT3, OCT2, MATE1, transporters MATE2-K, P-gp, or BCRP. Elimination Mass balance results Following IV administration of a single 1000 mg (approximately equivalent to 100 microCi =3.7 MBq) dose of [14C]-cefiderocol infused over 1 hour, total radioactivity was primarily (geometric mean: 98.59%) excreted in urine, with a minor amount (geometric mean: 2.79%) excreted into feces. Unchanged cefiderocol (90.57% of administered dose) was the major radioactive component detected in urine. A total of 21 cefiderocol-related components (M1 – M21 determined to be metabolites, impurities or degradation products) were detected in plasma, urine or feces. Clearance 5.18 (17.2%) L/hr [geometric mean (%CV)] Half-life 2 to 3 hours Metabolic pathway(s) Metabolism of cefiderocol is minimal. The most predominant metabolite, pyrrolidine chlorobenzamide, which is a degradation product of cefiderocol, accounted for 4.7% of the plasma AUC for total radioactivity, while other minor metabolites accounted for <2% of the plasma AUC for total radioactivity. Primary excretion Cefiderocol is primarily eliminated by the kidneys. Approximately 90% of a pathways (% dose) cefiderocol dose is excreted unchanged in urine, with 2.8% of the administered dose excreted in feces. Intrinsic Factors and Specific Populations Body weight No clinically meaningful differences in cefiderocol PK based on body weight were observed. Age No clinically significant differences in the pharmacokinetics of cefiderocol were observed based on age (18 to 93 years of age). Renal function Cefiderocol exposures increased with reduced renal function. Dose adjustment is needed in patients with CLcr less than 60 mL/min. Dose adjustment is also needed in patients receiving continuous renal replacement therapy (CRRT). Increased cefiderocol clearance has been observed in patients with CLcr 120 mL/min or greater. Dose adjustment is needed in patients with CLcr 120 mL/min or greater. Hepatic impairment The effect of hepatic impairment on the pharmacokinetics of cefiderocol is not evaluated. However, hepatic impairment is not expected to alter the elimination of cefiderocol because cefiderocol is mainly excreted by the kidneys.

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Reference ID: 4676324 NDA 209445 / S-002 Cefiderocol (Fetroja)

Characteristic Drug Information Drug Interaction Liability (Drug as Perpetrator) Inhibition/induction of • No concentration- or no time-dependent inhibitions of CYP1A2, 2B6, 2C8, metabolism 2C9, 2C19, 2D6, 2E1, and 3A4 by cefiderocol • No significant induction of CYP1A2, 2B6, and 3A4 Inhibition/induction of • No significant inhibitory effect on OATP1B1, MATE1, P-gp, BCRP, or BSEP. transporter systems • In vitro study suggested potential for cefiderocol to inhibit OAT1, OAT3, OCT1, OCT2, OATP1B3, and MATE2-K transporters (IC50 values ranged from 141 to 4850 μmol/L). • The results from a clinical drug-drug interaction study indicate that cefiderocol had no clinically meaningful effects on the PK of furosemide (substrate for OAT1 and OAT3), metformin (for OCT1, OCT2, and MATE2- K), and rosuvastatin (for OATP1B3). Abbreviations: AUC, area under the curve; BCRP, breast cancer resistance protein; BSEP, bile salt export pump; CLCR, creatinine clearance; Cmax, maximum plasma concentration; CV, coefficient of variation; CYP, cytochrome P450; HPLC/MS/MS, high- performance liquid chromatography-mass spectrometry; IC50, half maximal inhibitory concentration; IV, intravenous; MATE, multidrug and toxin extrusion protein; MBq, megabecquerel; MIC, minimum inhibitory concentration; OAT, organic anion transporter; OCT, organic cation transporter; PD, pharmacodynamics; P-gp, P-glycoprotein; PK, pharmacokinetics; q8h, every 8 hours; TQT, thorough QT 5.1. Nonclinical Assessment of Potential Effectiveness In Vitro Activity Cefiderocol has in vitro activity against several gram-negative pathogens including Enterobacterales and nonfermenting bacteria such as P. aeruginosa, A. baumannii, and S. maltophilia. Cefiderocol does not have any clinically relevant activity against gram-positive bacteria and anaerobic bacteria. The cefiderocol MIC required to inhibit 90% of tested isolates (MIC90) for Enterobacterales, P. aeruginosa, A. baumannii complex, B. cepacia complex, and S. maltophilia in surveillance studies were 1, 0.5, 2, 0.25, and 0.5 mcg/mL, respectively (see Section 18 Table 71). The cefiderocol MIC90 values against meropenem-resistant Enterobacterales and A. baumannii were four- or eight-fold higher than those of meropenem- susceptible isolates. On the other hand, the cefiderocol MIC90 values for meropenem-resistant P. aeruginosa were similar to those of the meropenem-susceptible isolates (see Section 18, Table 72). Cefiderocol demonstrated in vitro activity against certain Enterobacteriaceae genetically confirmed to contain the following: extended-spectrum β-lactamases (ESBLs; temoneira [TEM], sulfhydryl variable [SHV], cefotaximase [CTX-M], oxacillinase [OXA]); AmpC; AmpC-type ESBL (CMY); serine carbapenemases (such as K. pneumoniae carbapenemase [KPC], OXA-48); and metallo-carbapenemases (such as New Delhi metallo-β-lactamase [NDM] and Verona integron-encoded metallo-β-lactamase [VIM]). Cefiderocol demonstrated in vitro activity against certain P. aeruginosa genetically confirmed to contain VIM, imipenemase metallo-β-lactamase (IMP), Guiana extended-spectrum β-lactamase (GES), and AmpC, and against certain A. baumannii containing OXA-23, OXA-24/40, OXA-51, OXA-58, and AmpC. Cefiderocol has demonstrated in vitro activity against some K. pneumoniae isolates with OmpK35/36 porin deletion and some isolates of P. aeruginosa with outer membrane porin D (OprD) deletion. The activity of cefiderocol against efflux pump overexpressing strains isolates other than the P. aeruginosa multidrug efflux pump AB (MexAB)-OprM, MexCD-OprJ, MexEF-OprN, and MexXY-OprM cannot be concluded from the data provided (see Section 18).

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Reference ID: 4676324 NDA 209445 / S-002 Cefiderocol (Fetroja) In Vivo Activity In a neutropenic murine thigh infection model using a humanized dose (2 grams every 8 hours), cefiderocol demonstrated 1 log10 reduction in bacterial burden against most E. coli, K. pneumoniae, A. baumannii, and P. aeruginosa, including some carbapenemase-producing isolates with cefiderocol MICs of ≤4 mcg/mL and S. maltophilia isolates with cefiderocol MICs of ≤0.5 mcg/mL (see Section 18). In an immunocompetent rat pneumonia model, reduction in bacterial counts in the lungs of animals infected with K. pneumoniae with cefiderocol MICs ≤8 mcg/mL, P. aeruginosa with cefiderocol MICs ≤1 mcg/mL, and A. baumannii with cefiderocol MICs ≤2 mcg/mL was observed using humanized cefiderocol dose. In an immunocompetent murine urinary tract infection (UTI) model, cefiderocol reduced bacterial counts in the kidneys of mice infected with E. coli, K. pneumoniae, and P. aeruginosa isolates with MICs ≤1 mcg/mL. In an immunocompromised murine systemic infection model, cefiderocol increased survival in mice infected with Enterobacter cloacae, S. maltophilia, and B. cepacia isolates with MICs ≤0.5 mcg/mL compared to survival in untreated mice. In an immunocompetent murine systemic infection model, cefiderocol increased survival in mice infected with Serratia marcescens and P. aeruginosa isolates with MICs ≤1 mcg/mL compared to that in untreated mice. 6. Evidence of Benefit (Assessment of Efficacy)

6.1. Assessment of Dose and Potential Effectiveness The following proposed dosing regimen of cefiderocol is acceptable for the general patient population with HABP/VABP: • Cefiderocol 2 grams administered every 8 hours by intravenous (IV) infusion over 3 hours The same dose regimen has been approved for the general patient population with cUTI including pyelonephritis. The proposed dose regimen and the equivalent dose with adjustments for renal function [based on creatinine clearance (CLcr)] was evaluated in the Phase 3 trial APEKS-NP and compared to meropenem (2 grams every 8 hours infused over 3 hours). The APEKS-NP study met its primary endpoint by demonstrating that cefiderocol was noninferior to meropenem for the primary efficacy endpoint (Day 14 all-cause mortality in the mITT population) because the upper bound of the confidence interval of the difference in death rates at day 14 is less than the noninferiority margin (8.2% versus 12.5%).

Monte-Carlo simulations of cefiderocol PK at the proposed dosing regimens using the data from all clinical studies were performed to calculate the probability of PK/PD target attainments (PTA) with the target values of 75%, 90%, and 100% of time for which free drug concentration

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Reference ID: 4676324 NDA 209445 / S-002 Cefiderocol (Fetroja) in plasma exceeds MIC over dosing interval (fT > MIC) across an MIC range of 0.25 to 16 μg/mL. Monte-Carlo simulations were also performed to calculate PTA with free drug concentration in epithelial lining fluid (ELF) (%fT > MICELF). The results showed that PTA based on plasma concentrations (Table 6) and ELF concentrations (Table 7) were >90% at MIC of up to 4 μg/mL regardless of infection, suggesting that the proposed cefiderocol dosing regimen would provide adequate exposure of cefiderocol in patients with cUTI/AUP, BSI/sepsis, or HABP/VABP against bacteria with MIC ≤4 µg/mL.

Table 6. Overall Probability of Target Attainment (PTA) for 75%, 90%, and 100% fT > MIC in Plasma in Simulated Patients With Weighting for Distribution of CLcr in Phase 3 Studies

Source: Adapted from Table 2.7.2-12 from 2.7.2 Summary of Clinical Pharmacology – HABP/VABP

Table 7. Overall PTA for 75%, 90%, and 100% fT > MICELF in Epithelial Lining Fluid (ELF) in Simulated Patients With Weighting for Distribution of CLcr in Phase 3 Studies

Source: Table 4 from the Applicant’s study report of s-649266-cpk-005

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Reference ID: 4676324 NDA 209445 / S-002 Cefiderocol (Fetroja) 6.2. Design of Clinical Trials Intended to Demonstrate Benefit to Patients 6.2.1. Trial Design Results from the APEKS-NP trial served as the basis of the benefit evaluation. This trial was largely designed in accordance with recommendations given in FDA’s guidance for industry Hospital-Acquired Bacterial Pneumonia and Ventilator-Associated Bacterial Pneumonia: Developing Drugs for Treatment (June 2020). The guidance states that randomized, double- blind, active-controlled, NI trials are appropriate for evaluating the efficacy and safety of an experimental treatment. Appropriate primary endpoints include ACM assessed at a fixed time point between day 14 and day 28 inclusive. For NI margins, the guidance set the M1 margin (i.e., improvement in survival rate due to use of the active control treatment instead of placebo) at 20% and recommended an M2 margin of 10% (i.e., the experimental treatment is considered noninferior to the active control if its survival rate is within 10% of the active control rate). As discussed below, the trial’s main divergence from guidance recommendations consisted in setting the M2 margin at 12.5% rather than 10%. The APEKS-NP trial was a phase 3, randomized, double-blind, multisite, NI trial with an experimental cefiderocol arm and an active control meropenem arm. Its principal aim with regard to efficacy was to evaluate whether cefiderocol is noninferior to meropenem as a treatment for nosocomial pneumonia (NP) caused by gram-negative bacteria. Both treatments were administered intravenously for an anticipated 7 to 14 days, with possible extension up to 21 days. Linezolid was administered in both arms to provide coverage of methicillin-resistant S. aureus and in the cefiderocol arm to provide coverage for gram-positive bacteria. Three hundred subjects were randomized (148 to cefiderocol, 152 to meropenem) at 77 sites. Randomization was stratified by infection type (HABP, VABP, and HCABP) and by Acute Physiology and Chronic Health Evaluation (APACHE) II score at baseline (≤15 versus ≥16) The trial employed a group sequential design, with interim analyses planned for when about 50 and then 150 subjects had been randomized and completed treatment and follow-up. See Section 15 for additional details. Clinical and microbiological outcomes were assessed at the following occasions: • Early assessment (EA): day 3 or 4 • End of treatment (EOT): end of last infusion (same calendar day or +1 day) • Test-of-cure (TOC): EOT +7 days (+/- 2 days) • Follow-up (FU): EOT +14 days (+/- 3 days) Further details are provided in Section 14. 6.2.2. Eligibility Criteria Section 15 gives the full sets of inclusion and exclusion criteria. Key inclusion criteria included: age 18 years or greater; diagnosis of HABP, VABP, or HCABP; chest X-ray showing the presence of new or progressive infiltrate(s) suggestive of bacterial pneumonia; and suspected gram-negative infection involving the lower respiratory tract.

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Reference ID: 4676324 NDA 209445 / S-002 Cefiderocol (Fetroja) Key exclusion criteria included: known or suspected community-acquired bacterial pneumonia, atypical pneumonia, viral pneumonia, or chemical pneumonia; hypersensitivity to cephalosporins or to carbapenems; gram-negative infection caused by carbapenem-resistant pathogen; and an APACHE II score >35. 6.2.3. Statistical Analysis Plan The Applicant and the review division agreed on the APEKS-NP statistical analysis plan prior to the trial completion. Of particular note, in an April 25, 2016 letter to the Applicant, under IND 116787, the division wrote, “Your proposal to use a noninferiority (NI) margin of 12.5% will be adequate to support approval with a limited use statement.” Note that this NI margin still maintained an appreciable proportion of the guidance’s M1 value of 20%. Efficacy Endpoints • Primary: ACM at day 14 (since first administration of study drug). • Key secondary: — Microbiological outcome at TOC: eradication of all baseline gram-negative pathogens versus persistence of any such pathogens. If it was not possible to obtain a clinical culture and the subject had a successful clinical outcome, then the response was presumed to be eradication. This was only defined for subjects with a gram- negative pathogen detected at baseline. — Clinical outcome at TOC: per investigator assessment, cure (resolution or substantial improvement in baseline signs and symptoms of pneumonia such that no antibacterial therapy needed) versus failure (persistence or worsening of baseline signs and symptoms and/or new signs/symptoms or death). • Other secondary endpoints included: ACM at day 28 and end of study (EOS). Microbiological outcome and clinical outcome at EA, EOT, and FU. Primary Population The primary analysis population was the mITT population. The full intention-to-treat (ITT) population included all randomized subjects who received at least one dose of study drug (cefiderocol 148, meropenem 150, total 298). The mITT population included all ITT subjects who met either of the following (cefiderocol 145, meropenem 147, total 292, 98.0% of the ITT population): • Evidence of a gram-negative infection of lower respiratory tract. • Evidence of infection of lower respiratory tract but culture or other tests didn’t provide a microbiological diagnosis. Significance Levels for Testing The two-sided alpha level used was 0.0496 and was adjusted for the two interim analyses that were conducted. The study did not stop early. Correspondingly, 95.04% (rather than 95%) confidence intervals (CIs) were reported.

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Reference ID: 4676324 NDA 209445 / S-002 Cefiderocol (Fetroja) Testing Noninferiority of Cefiderocol to Meropenem Regarding the Primary Endpoint An NI margin of 12.5% was used. This meant that cefiderocol was considered noninferior to meropenem if the difference between its ACM rate at day 14 and the corresponding meropenem rate was less than 12.5%. Otherwise, cefiderocol was not considered noninferior to meropenem. The Cochran-Mantel-Haenszel stratum-weighted estimator (described in Section 15) was used to perform the test and construct CIs. Testing and Analyzing Secondary Endpoints If statistical significance was achieved for the primary NI test, then (i) the superiority of cefiderocol to meropenem regarding microbiological outcome at TOC was tested. If significant, then (ii) the superiority regarding clinical outcome at TOC was tested. Then, if significant, (iii) the superiority regarding ACM at day 14 was tested. If statistical significance was not achieved at this point in the testing sequence, all testing was halted and subsequent secondary efficacy analyses were considered exploratory. Additional statistical details are provided in Section 16. 6.3. Results of Analyses of Clinical Trials/Studies Intended to Demonstrate Benefit to Patients The following table examines between-arm balance on demographic and baseline clinical status characteristics in the ITT population. The ITT population was identical to the safety population and contained six more subjects than the mITT population (298 total subjects to 292 total subjects [cefiderocol 145, meropenem 147]; mITT population included 98.0% of the ITT population). The six subjects in the ITT population who were not in the mITT population did not have evidence of a lower respiratory tract infection. The table results were similar to results for the mITT population.

Table 8. Baseline Demographic and Clinical Characteristics, ITT Population, APEKS-NP Trial Cefiderocol Meropenem Total Characteristic N=148 N=150 N=298 Sex Male 101 (68.2) 104 (69.3) 205 (68.8) Female 47 (31.8) 46 (30.7) 93 (31.2) Age, years Mean (SD) 64.7 (14.5) 65.6 (15.1) 65.2 (14.8) Median (min, max) 67.0 (18.0, 91.0) 68.0 (20.0, 94.0) 67.0 (18.0, 94.0) Age group ≥65 years 83 (56.1) 92 (61.3) 175 (58.7) <65 years 65 (43.9) 58 (38.7) 123 (41.3) <75 years 108 (73.0) 103 (68.7) 211 (70.8) ≥75 years 40 (27.0) 47 (31.3) 87 (29.2) Ethnicity Not Hispanic or Latino 140 (94.6) 139 (92.7) 279 (93.6) Not reported 4 (2.7) 8 (5.3) 12 (4.0) Hispanic or Latino 4 (2.7) 3 (2.0) 7 (2.3)

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Reference ID: 4676324 NDA 209445 / S-002 Cefiderocol (Fetroja)

Cefiderocol Meropenem Total Characteristic N=148 N=150 N=298 Race White 102 (68.9) 100 (66.7) 202 (67.8) Asian 44 (29.7) 44 (29.3) 88 (29.5) Other 2 (1.4) 4 (2.7) 6 (2.0) Black or African American 0 1 (0.7) 1 (0.3) Region Europe 99 (66.9) 100 (66.7) 199 (66.8) Asia-Pacific 43 (29.1) 44 (29.3) 87 (29.2) North America 6 (4.1) 6 (4.0) 12 (4.0) Clinical diagnosis as collected VABP 60 (40.5) 65 (43.3) 125 (41.9) HABP 60 (40.5) 61 (40.7) 121 (40.6) HCABP 28 (18.9) 24 (16.0) 52 (17.4) Ventilation status at randomization Ventilated 91 (61.5) 87 (58.0) 178 (59.7) Nonventilated 57 (38.5) 63 (42.0) 120 (40.3) Ventilation status at randomizationa Ventilated 91 (61.5) 87 (58.0) 178 (59.7) VABP 59 (39.9) 64 (42.7) 123 (41.3) HABP 22 (14.9) 21 (14) 43 (14.4) HCABP 10 (6.8) 2 (1.3) 12 (4) Nonventilated 57 (38.5) 63 (42.0) 120 (40.3) HABP 38 (25.7) 40 (26.7) 78 (26.2) HCABP 18 (12.2) 22 (14.7) 40 (13.4) VABP 1 (0.7) 1 (0.7) 2 (0.7) Creatinine clearance renal grading group >120 ml/min 22 (14.9) 26 (17.3) 48 (16.1) >80-120 ml/min 33 (22.3) 35 (23.3) 68 (22.8) >50-80 ml/min 44 (29.7) 37 (24.7) 81 (27.2) 30-50 ml/min 29 (19.6) 32 (21.3) 61 (20.5) <30 ml/min 20 (13.5) 20 (13.3) 40 (13.4) Creatinine clearance Mean (SD) 77.8 (55.1) 82.1 (56.2) 79.9 (55.6) Median (min, max) 65.2 (4.7, 305.8) 68.9 (7.4, 281.2) 67.7 (4.7, 305.8) Empiric treatment failure status Yes 49 (33.1) 48 (32.0) 97 (32.6) No 99 (66.9) 102 (68.0) 201 (67.4) Prior therapy Yes 107 (72.3) 103 (68.7) 210 (70.5) No 41 (27.7) 47 (31.3) 88 (29.5) CPIS category <6 74 (50.0) 91 (60.7) 165 (55.4) 6-7 60 (40.5) 40 (26.7) 100 (33.6) 7-9 12 (8.1) 16 (10.7) 28 (9.4) >9 2 (1.4) 3 (2.0) 5 (1.7) ICU admission flag Yes 103 (69.6) 99 (66.0) 202 (67.8) No 45 (30.4) 51 (34.0) 96 (32.2) Severity of disease Mild 4 (2.7) 7 (4.7) 11 (3.7) Moderate 73 (49.3) 93 (62.0) 166 (55.7) Severe 71 (48.0) 50 (33.3) 121 (40.6)

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Reference ID: 4676324 NDA 209445 / S-002 Cefiderocol (Fetroja)

Cefiderocol Meropenem Total Characteristic N=148 N=150 N=298 SOFA score (ventilated) Mean (SD) 6.1 (2.8) 6.3 (3.1) 6.2 (3.0) Median (min, max) 6.0 (1,13) 6.0 (0,16) SOFA score (nonventilated) Mean (SD) 2.8 (2.5) 2.7 (2.5) 2.7 (2.78) Median (min, max) 2 (0,12) 2 (0,7) 2 (0,12) Total APACHE II score as collected Mean (SD) 16.1 (6.1) 16.3 (6.9) 16.2 (6.5) Median (min, max) 15.0 (3.0, 34.0) 15.0 (4.0, 35.0) 15.0 (3.0, 35.0) Source: adsl.xpt; Software: Python All values are expressed as n (%) unless specified otherwise. a Ventilation status by clinical diagnosis. Abbreviations: APACHE, Acute Physiology and Chronic Health Evaluation; CPIS, clinical pulmonary infection score; HABP, hospital- acquired bacterial pneumonia; HCABP, healthcare-associated bacterial pneumonia; ICU, intensive care unit; ITT, intention-to-treat; SD, standard deviation; SOFA, Sequential Organ Failure Assessment; VABP, ventilator-associated bacterial pneumonia Table 9 examines between-arm balance on baseline microbiological characteristics in the ITT population. Again, results were similar for the mITT population.

Table 9. Baseline Microbiology Characteristics, ITT Population, APEKS-NP Trial Cefiderocol Meropenem Total Characteristic N=148 N=150 N=298 Baseline pathogen type Gram-negative pathogens 113 (76.4) 105 (70.0) 218 (73.2) Mixed pathogens 11 (7.4) 22 (14.7) 33 (11.1) Culture negative 12 (8.1) 8 (5.3) 20 (6.7) No pathogen 3 (2.0) 5 (3.3) 8 (2.7) No respiratory sample 3 (2.0) 4 (2.7) 7 (2.3) Gram-positive pathogens 3 (2.0) 3 (2.0) 6 (2.0) Fungal pathogens 1 (0.7) 1 (0.7) 2 (0.7) Missing 2 (1.4) 2 (1.3) 4 (1.3) Top 5 baseline gram-negative pathogens Klebsiella pneumoniae 48 (32.4) 44 (29.3) 92 (30.9) Pseudomonas aeruginosa 24 (16.2) 24 (16.0) 48 (16.1) Acinetobacter baumannii 23 (15.5) 24 (16.0) 47 (15.8) Escherichia coli 19 (12.8) 22 (14.7) 41 (13.8) Enterobacter cloacae 7 (4.7) 8 (5.3) 15 (5.0) Baseline blood culture status Negative 124 (83.8) 118 (78.7) 242 (81.2) Positive 13 (8.8) 16 (10.7) 124 (50.0) Gram-negative 8 (5.4) 10 (6.7) 18 (6.0) Gram-positive 5 (3.4) 6 (4.0) 11(3.7) Blood culture not done 11 (7.4) 16 (10.7) 27 (9.1) Baseline gram-negative pathogens number 0 24 (16.2) 23 (15.3) 47 (15.8) 1 95 (64.2) 96 (64.0) 191 (64.1) 2 25 (16.9) 26 (17.3) 51 (17.1) 3 2 (1.4) 4 (2.7) 6 (2.0) >3 2 (1.4) 1 (0.7) 3 (1.0)

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Cefiderocol Meropenem Total Characteristic N=148 N=150 N=298 Gram-negative bacteremia pathogens Klebsiella pneumoniae 3 (2.0) 4 (2.7) 7 (2.3) Serratia marcescens 2 (1.4) 1 (0.7) 3 (1.0) Burkholderia cenocepacia 1 (0.7) 1 (0.7) 2 (0.7) Acinetobacter anitratus; Escherichia coli 1 (0.7) 0 1 (0.3) Acinetobacter baumannii 1 (0.7) 0 1 (0.3) Enterobacter cloacae 0 1 1 (0.3) Escherichia coli 0 1 (0.7) 1 (0.3) Providencia stuartii 0 1 (0.7) 1 (0.3) Pseudomonas aeruginosa 0 1 (0.7) 1 (0.3) Source: adsl.xpt; Software: Python All values are expressed as n (%) unless specified otherwise. Abbreviations: ITT, intention-to-treat In addition to the baseline characteristics above, the frequency of underlying medical conditions were similar between the treatment groups, as noted in Table 10 below.

Table 10. Medical History in ≥10% of Patients in Either Treatment Group, ITT Population, APEKS- NP Trial Cefiderocol Meropenem Dictionary-Derived Term N=148 N=150 Anemia 28 (18.9) 27 (18.0) Atrial fibrillation 33 (22.3) 40 (26.7) Cardiac failure, chronic 14 (9.5) 17 (11.3) Coronary artery disease 24 (16.2) 20 (13.3) Myocardial ischemia 18 (12.2) 26 (17.3) Pneumonia 16 (10.8) 22 (14.7) Diabetes mellitus 22 (14.9) 21 (14.0) Hypokalemia 28 (18.9) 25 (16.7) Type 2 diabetes mellitus 23 (15.5) 14 (9.3) Chronic kidney disease 19 (12.8) 17 (11.3) Acute respiratory failure 18 (12.2) 15 (10.0) Chronic obstructive pulmonary disease 41 (27.7) 31 (20.7) Hypertension 96 (64.9) 103 (68.7) Source: Reviewer Table, created in JMP Clinical All values are expressed as n (%) unless specified otherwise Abbreviations: ITT, intention-to-treat The frequency of diabetes mellitus (DM) and type 2 diabetes mellitus was 30% and 23% in the cefiderocol and meropenem groups, respectively. Of note, tobacco use was reported in 1.4% and 2.7% in the cefiderocol and meropenem groups, respectively. Of 357 patients screened, 57 were considered screening failures, and 300 were randomized. Two patients in the meropenem group were not treated, and thus, the total number of patients treated was 298 (n=148 in cefiderocol and 150 in the meropenem group). A slightly higher number of patients discontinued the study and received fewer than 7 days of study treatment in the cefiderocol group than in the meropenem group; the majority were due to deaths and treatment- emergent AEs (TEAEs).

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Table 11. Patient Disposition, ITT Population, APEKS-NP Trial Cefiderocol Meropenem Total Disposition Outcome N=148 N=152 N=300 Subjects randomized 148 (100.0) 152 (100.0) 300 (100.0) Subjects randomized but not treated 0 2 (1.3) 2 (0.7) Subjects treated 148 (100.0) 150 (98.7) 298 (99.3) Completed study 106 (71.6) 112 (73.7) 218 (72.7) Discontinued study 42 (28.4) 40 (26.3) 82 (27.3) Adverse event 0 1 (0.7) 1 (0.3) Lack of efficacy 1 (0.7) 0 1 (0.3) Withdrawal by subject 2 (1.4) 3 (2.0) 5 (1.7) Protocol deviation 0 0 0 Recovery 0 1 (0.7) 1 (0.3) Lost to follow-up 0 0 0 Death 39 (26.4) 34 (22.4) 73 (24.3) Other 0 1 (0.7) 1 (0.3) Received less than 7 days of study treatment 18 (12.2) 15 (9.9) 33 (11.0) Adverse event 10 (55.6) 10 (66.7) 20 (6.7) Lack of efficacy 2 (11.1) 1 (6.7) 3 (1.0) Withdrawal by subject 1 (5.6) 0 1 (0.3) Death 4 (22.2) 1 (6.7) 5 (1.6) Meropenem resistant 0 2 (13.3) 3 (1.0) Clinical cure 0 1 (6.7) 1 (0.3) Palliative care 1 (3.6) 0 1 (0.3) Source: Applicant All values are expressed as n (%) unless specified otherwise Abbreviation: ITT, intention-to-treat; N, number of subjects; n, number of subjects with at least one event. Table 12 examines length of treatment in days in the mITT population. The intended length of treatment for both arms was 7 to 14 days, with treatment up to 21 days allowed if clinically indicated. In the meropenem arm, 73.5% of subjects received the intended duration of treatment, while 66.2% of subjects did in the cefiderocol arm. Somewhat larger proportions of subjects in the cefiderocol arm received less than the intended duration and received more than the intended duration than in the meropenem arm.

Table 12. Length of Treatment in Days in the mITT Population, APEKS-NP Trial Length of Treatment Cefiderocol Meropenem Median 10 9 <7 days 17 (11.7) 14 (9.5) 7-14 days 96 (66.2) 108 (73.5) 15-21 days 30 (20.7) 24 (16.3) ≥22 days 2 (1.4) 1 (0.7) Source: adsl.xpt. All values are expressed as n (%) unless specified otherwise Notes. The mITT population included 292 subjects: the cefiderocol arm included 145 subjects and the meropenem arm included 147 subjects. Abbreviations: mITT, modified intention-to-treat Table 13 presents the analyses of ACM at day 14, the primary endpoint, and ACM at day 28. Because the upper bound of the CI for the difference in death rates at day 14 is less than the NI margin (8.2% versus 12.5%), the NI of cefiderocol to meropenem is demonstrated with respect to the primary endpoint. Note that the observed meropenem mortality rate of 11.6% at day 14 is close to the rate of 10% the Applicant assumed in its sample size calculations.

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Table 13. All-Cause Mortality at Days 14 and 28 in the mITT Population, APEKS-NP Trial Endpoint Cefiderocol Meropenem Difference ACM at day 14 18/145 (12.4) 17/146 (11.6) 0.8 (-6.6, 8.2)a ACM at day 28 30/143 (21.0) 30/146 (20.5) 0.5 (-8.7, 9.8) Source: adsl.xpt. All values are expressed as n/N’ (%) except those in Difference column, which are expressed as % (CI). Notes. Estimates of difference in mortality rates and construction of confidence intervals derived from use of Cochran-Mantel- Haenszel (CMH) stratum-weighted estimator, with strata based on Apache II score at randomization (≤15 vs. ≥16). Per Applicant, subjects with unknown survival status are not included in analyses. 95.04% (rather than 95%) confidence intervals are reported, per adjustment in alpha level due to performance of multiple interim analyses. The mITT population included 292 subjects: the cefiderocol arm included 145 subjects and the meropenem arm included 147 subjects. a The null hypothesis that cefiderocol is inferior to meropenem (with respect to the 12.5 noninferiority margin) was rejected, 2-sided p =.002. No hypothesis tests were performed with respect to ACM at day 28. Abbreviations: ACM, all-cause mortality; CI, confidence interval; mITT, modified intention-to-treat; n, number of subjects who died by the indicated timepoint; N’, number of subjects with known survival status at the indicated timepoint Sensitivity analyses of the ACM endpoints are presented in Section 16 and are consistent with the results presented so far. As also discussed in that section, the extent of missing data was negligible and had little impact on results. Section 16 also reports results of subgroup analyses of ACM at 14 days. Table 14 presents the results of analyses of the two key secondary endpoints, microbiological outcome at TOC and clinical outcome at TOC. Microbiological outcome endpoints are only defined for subjects who had gram-negative pathogens detected at baseline. Of the 145 mITT subjects in the cefiderocol arm, 124 (85.5%) had such pathogens detected at baseline; of the 147 mITT subjects in the meropenem arm, 127 (86.4%) had such pathogens detected at baseline. As discussed above, because cefiderocol NI was demonstrated with regard to the primary endpoint, the superiority/nonsuperiority of cefiderocol versus meropenem was tested with regard to the first key secondary endpoint, microbiological outcome at TOC. This test yielded a statistically nonsignificant result, which, per the Applicant’s testing scheme, meant that no further hypothesis testing was to be conducted and all subsequent statistical analyses were to be considered exploratory in nature. The table shows that, for both key secondary endpoints, the treatment success rates for the two arms were similar, with slightly lower rates for cefiderocol.

Table 14. Key Secondary Endpoints at Test of Cure in the mITT Population, APEKS-NP Trial Endpoint Cefiderocol Meropenem Difference Microbiological eradication 59/124 (47.6) 61/127 (48.0) -1.4 (-13.5, 10.8)a Clinical cure 94/145 (64.8) 98/147 (66.7) -2.0 (-12.5, 8.5) Source: adsl.xpt; admbo.xpt; adclo.xpt. All values are expressed as n/N’ (%) except those in the Difference column, which are expressed as % (CI). Notes. The test-of-cure assessment occurred 7 days (+/- 2) after the end of treatment. Estimates of difference in mortality rates and construction of confidence intervals derived from use of Cochran-Mantel-Haenszel (CMH) stratum-weighted estimator, where subjects with unknown microbiological/clinical status are considered treatment failures. 95.04% (rather than 95%) confidence intervals are reported, due to adjustment in alpha level due to performance of multiple interim analyses. The mITT population included 292 subjects: the cefiderocol arm included 145 subjects and the meropenem arm included 147 subjects. Abbreviations: CI, confidence interval; mITT, modified intention-to-treat; n, number of subjects who were treatment successes; N’, number of subjects in arm for whom the endpoint is defined; See Section 16 for results of analyses of microbiological outcome and clinical outcome at other time points. These results and the subgroup analysis results are consistent with the results presented in this section.

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Reference ID: 4676324 NDA 209445 / S-002 Cefiderocol (Fetroja) 6.4. Review Issues Relevant to the Evaluation of Benefit 6.4.1. Important Review Issue #1 Relevant to Benefit Issue Confounding of treatment effect by prior and concomitant antibacterial drugs Background Since there were a limited number of subjects in the APEKS-NP trial, the quality of clinical data was an important review issue. Patients who were included in the trial due to failed empiric therapy under criterion 9(b)(ii), or protocol violations resulting in the administration of prior and and/or concomitant gram-negative antibacterial therapy may have had the potential to reduce the assay sensitivity in this NI trial and artificially drive results in the two groups toward similar outcomes. Assessment The following sensitivity analyses were performed to isolate patient subpopulation(s) in the mITT population who would best demonstrate the treatment effect of cefiderocol relative to meropenem with minimal confounding: 1) subjects who received 24 hours or less of effective prior antibacterial therapy (during the previous 72 hours prior to randomization) and less than 72 hours of effective concomitant antibacterial therapy; 2) subjects who received 24 hours or less of effective prior antibacterial therapy (during the previous 72 hours prior to randomization); 3) subjects who received less than 72 hours of effective concomitant antibacterial therapy. Potentially effective antibacterial therapy was defined as IV, oral, or inhaled therapy which had activity against gram-negative bacteria. If the pathogen was intrinsically resistant or resistant per the MIC or surrogate MIC, the patient was not excluded. If MIC results or the concomitant or prior antibacterial drug identification were not available, the pathogen was assumed to be susceptible. Patients were excluded if they had greater than or equal to 72 hours of concomitant antibacterial therapy from time to first dose of study drug up to but not including the day of TOC. This review was conducted by the Applicant upon request from the Division prior to NDA submission.

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Table 15. Sensitivity Analysis of All-Cause Mortality at Day 14 After Start of Study Treatment Excluding Subjects With Potentially Effective Antibacterial Therapya Patients Who Did Not Receive the Following Cefiderocol Meropenem Potentially Effective N=145 N=147 Treatment Comparisonb Antibacterial Therapy n/N’ (%) n/N’ (%) Difference (%) 95% CIc Prior or concomitant therapy 15/126 (11.9) 16/128 (12.5) -0.4 (-8.3, 7.6) Prior therapy 15/137 (10.9) 16/138 (11.6) -0.5 (-7.9, 6.9) Concomitant therapy 18/134 (13.4) 17/135 (12.6) 1.0 (-7.0, 8.9) Source: Adapted from Applicant’s response to IR dated February 24, 2020 Day 14 ACM = all-cause mortality at Day 14 since first infusion of study drug a Effective prior antibacterial therapy include systemic antibacterial therapy which have activity for gram-negative bacteria and were given for >24 hours during the 72 hours prior to first dose of study drug and effective concomitant antibacterial therapy include systemic antibacterial therapy which has activity for gram-negative bacteria and were taken for >=72 hours any time after first infusion of study drug until TOC. b Treatment difference (cefiderocol minus meropenem) is the adjusted estimate of the difference in the all-cause mortality rate at Day 14 between the 2 treatment arms based on Cochran-Mantel Haenszel weights using APACHE II score (≤15 and ≥16) as the stratification factor. c The 95% CI (2-sided) is based on a stratified analysis using Cochran-Mantel Haenszel weights using APACHE II score (≤15 and ≥16) as the stratification factor. The CI is calculated using a normal approximation to the difference between 2 binomial proportions (Wald method). Abbreviations: ACM, all-cause mortality; APACHE, Acute Physiology and Chronic Health Evaluation; CI, confidence interval; N, number of subjects in the analysis set; n, number of subjects who died; N’, number of subjects with known survival status; TOC, test of cure Conclusions As displayed in Table 15, these analyses are consistent with the overall study analyses. In the subgroups of patients who did not receive effective prior, concomitant, or either prior or concomitant antibacterial therapy, NI was demonstrated in day 14 ACM between the cefiderocol and meropenem groups. 6.4.2. Important Review Issue #2 Relevant to Benefit Issue Does meropenem nonsusceptibility contribute to the demonstration above that cefiderocol is noninferior to meropenem? Discussion In the preceding discussion of benefit, statistical analysis of the primary endpoint, ACM at 14 days, showed that cefiderocol is noninferior to meropenem with respect to this endpoint. In theory, this result could largely be driven by meropenem-nonsusceptibility, i.e., by the possibility that a significant proportion of subjects in the meropenem arm were unlikely to benefit from meropenem. This is concerning in an NI trial because it is important that the active control have its expected activity in order to make the NI conclusions meaningful. We examine this possibility by redoing key efficacy analyses with restrictions for subjects with baseline pathogens known to be susceptible to meropenem. Here, a subject is included in the analysis if, for all gram-negative pathogens detected at baseline, the baseline meropenem MIC is ≤8 mcg/mL. If the baseline meropenem MIC is greater than 8 mcg/mL or is missing for at least one gram- negative pathogen, then the subject is excluded from the analyses reported below.

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Reference ID: 4676324 NDA 209445 / S-002 Cefiderocol (Fetroja) Assessment Of the 292 subjects in the mITT population, 172 (58.9%) were known to be susceptible to meropenem. The cefiderocol arm included 89 such subjects, and the meropenem arm included 83 subjects. The following table (Table 16) presents the results of key efficacy analyses when restricted to subjects known to be susceptible to meropenem. The key takeaway is that the NI of cefiderocol to meropenem, with regard to the primary endpoint, is again demonstrated, as the relevant CI upper bound of 7.4% is less than the NI margin of 12.5%. For all three endpoints reported in the table, the estimated differences in rates slightly favor cefiderocol.

Table 16. Key Endpoint Analyses Restricted to Subjects With Known Meropenem Susceptibility, APEKS-NP Trial Endpoint Cefiderocol Meropenem Difference ACM at day 14 9/89 (10.1) 10/82 (12.2) -2.1 (-11.6, 7.4) ACM at day 28 16/87 (18.4) 16/82 (19.5) -1.1 (-13.0, 10.7) Clinical outcome at TOC 60/89 (67.4) 53/83 (63.9) 3.6 (-10.7, 17.8) Source: adsl.xpt, adclo.xpt, adms.xpt. All values are expressed as n/N’ (%) except those in the Difference column, which are expressed as % (CI). Notes. Estimates of difference in mortality/clinical cure rates are equal to differences in rates per arm. Per Applicant, subjects with unknown survival status are not included in ACM analyses and subjects with indeterminate clinical outcome values are considered clinical failures. Wald confidence intervals are computed. 95.04% (rather than 95%) confidence intervals are reported, per adjustment in alpha level due to performance of multiple interim analyses. Abbreviations: ACM, all-cause mortality; CI, confidence interval; n, number of subjects who died by/experienced clinical cure at the indicated timepoint; N’, number of subjects with known survival status at the indicated timepoint (ACM rows), N’, all subjects with known susceptibility (clinical outcome row); TOC, test-of-cure The following tables (Table 17, Table 18) examine outcomes on three key endpoints by baseline pathogen. These tables also differ from the preceding table by restricting focus to subjects known to be susceptible for at least one baseline gram-negative pathogen rather than to subjects known to be susceptible to all of their baseline pathogens. Hence, the tables draw from a wider set of subjects than the preceding table. Each table row reports the outcomes of subjects known to be susceptible to the row’s pathogen. The per-pathogen subsamples are not large, so strong signals would be hard to discern, but the tables provide no evidence of the inferiority of cefiderocol to meropenem with respect to the key endpoints.

Table 17. All-Cause Mortality by Baseline Pathogen, Restricted to Baseline Pathogens With Meropenem Susceptibility, APEKS-NP Trial Day 14 All-Cause Mortality Day 28 All-Cause Mortality Baseline Group or Pathogen Fetroja Meropenem Fetroja Meropenem Klebsiella pneumoniae 4/38 (10.5) 4/36 (11.1) 8/38 (21.1) 9/36 (25.0) Pseudomonas aeruginosa 2/20 (10.0) 3/16 (18.8) 2/20 (10.0) 4/16 (25.0) Acinetobacter baumannii complex 1/8 (12.5) 0/9 (0.0) 2/7 (28.6) 0/9 (0.0) Escherichia coli 3/18 (16.7) 3/21 (14.3) 5/18 (27.8) 4/21 (19.0) Enterobacter cloacae complex 1/9 (11.1) 2/10 (20.0) 2/9 (22.2) 3/10 (30.0) Serratia marcescens 1/8 (12.5) 0/4 (0.0) 2/8 (25.0) 0/4 (0.0) Proteus mirabilis 0/2 (0.0) 1/5 (20.0) 0/2 (0.0) 1/5 (20.0) Source: adsl.xpt, adms.xpt. All values are expressed as n/N’ (%). Note: Per Applicant, subjects with unknown survival status are excluded. Abbreviations: n, number of subjects who died by the indicated timepoint; N’, number of subjects known to be meropenem suscept ble for the pathogen and with known survival status at the indicated timepoint

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Reference ID: 4676324 NDA 209445 / S-002 Cefiderocol (Fetroja) See Section 16 for a sensitivity analysis that treats unknown survival status as death, as is done in the label.

Table 18. Clinical Outcome at Test of Cure by Baseline Pathogen, Restricted to Baseline Pathogens With Known Meropenem Susceptibility, APEKS-NP Trial Clinical Outcome at TOC Baseline Group or Pathogen Fetroja Meropenem Klebsiella pneumoniae 24/38 (63.2) 23/36 (63.9) Pseudomonas aeruginosa 13/20 (65.0) 13/17 (76.5) Acinetobacter baumannii complex 6/8 (75.0) 7/9 (77.8) Escherichia coli 12/18 (66.7) 13/21 (61.9) Enterobacter cloacae complex 5/9 (55.6) 5/10 (50.0) Serratia marcescens 5/8 (62.5) 3/4 (75.0) Proteus mirabilis 1/2 (50.0) 1/5 (20.0) Source: adsl.xpt, adclo.xpt, adms.xpt. All values are expressed as n/N’ (%). Note: Per Applicant, subjects with indeterminate clinical outcome values are considered clinical failures. Abbreviations: n, number of subjects who experienced clinical cure at test-of-cure visit; N, number of subjects known to be meropenem susceptible for the pathogen; TOC, test-of-cure Conclusion The results of analyses reported in the preceding three tables provide no evidence that the finding of cefiderocol NI to meropenem was driven by meropenem nonsusceptibility. 6.4.3. Important Review Issue #3 Relevant to Benefit Issue Inclusion of Acinetobacter spp., S. maltophilia, and B. cepacia in the indication and List 1 of the microbiology section of the labeling. In addition to in vitro data, organisms included in this list must be relevant to HABP/VABP and be identified in sufficient numbers in the clinical trial for the HABP/VABP indication. Inclusion of A. baumannii in labeling was a challenging issue. While A. baumannii was the third most common pathogen identified in the APEKS-NP study, approximately 66% of Acinetobacter isolates were meropenem non-susceptible (MIC >8 mcg/ml, based on the dose of 2 gram infused over 3 hours, every 8 hours). The APEKS-NP study was designed to exclude carbapenem- resistant pathogens since the comparator was meropenem. When excluding patients with meropenem nonsusceptible (MIC >8 mcg/ml) isolates or isolates with unknown susceptibility in both treatment arms, there were only eight patients in the cefiderocol and nine patients in the meropenem group. Generally, for inclusion of an organism in the indication, clinical data in the test arm on at least 10 isolates is expected. An additional concern was that in the subgroup of patients with A. baumannii complex at baseline, the mortality at day 14, 28 and clinical cure at TOC were numerically disfavorable in the cefiderocol group, as noted in Table 17 and Table 18. Similar findings were also seen in the subgroup of isolates that were not susceptible to meropenem, a subgroup where one would have expected the results to be in favor of cefiderocol. There were 51 patients with A. baumannii complex at baseline, of which 17 (33.3%) patients had isolates susceptible to meropenem (MIC ≤8 mcg/mL, based on meropenem 2 grams every 8 hours). Among these 51 patients, all-cause mortality at day 14 was 5/26 (19.2%) in Fetroja and 4/25 (16.0%) in the meropenem treatment group and at day 28 was 9/26 (34.6%) in Fetroja and 32 Integrated Review Template, version date 2019/10/16

Reference ID: 4676324 NDA 209445 / S-002 Cefiderocol (Fetroja) 6/25 (24.0%) in the meropenem treatment group. The clinical cure rates at the TOC visit were 14/26 (53.8%) in the Fetroja and 15/25 (60.0%) in the meropenem treatment group. Figure 1 shows day 14 ACM in all patients with Acinetobacter infections including unspeciated Acinetobacter and A. junii and in subgroups of patients with increasing MIC to meropenem. In the subgroups of patients with MIC to meropenem ranging from >16 to >64 mcg/mL, day 14 ACM may have favored the cefiderocol group. No deaths occured through day 28 in the small subgroup of patients who were treated with cefiderocol (n=5) with Acinetobacter spp. at baseline with a meropenem MIC >64 mcg/ml. Further information on mortality by pathogen is provided in Section 7.7.

Figure 1. 14-Day ACM Among Subjects With Acinetobacter Infections at Baseline by MIC to Meropenem, APEKS-NP

Source: Applicant’s justification document for inclusion of A. baumannii complex The data suggests a trend in 14-day ACM to favor cefiderocol as the MIC to meropenem increases. This is anticipated, since meropenem’s activity against Acinetobacter is expected to be inversely proportional to the MIC. Figure 1 reflects that cefiderocol likely has efficacy in treatment of patients with Acinetobacter HABP/VABP. Taking into consideration all the available data on Acinetobacter HABP/VABP in the sNDA, A. baumannii complex was included in the indication and List 1 in labeling. While, it is difficult to draw any conclusions from these posthoc subgroup analysis of the overall population, it is important that the limitations of these data be communicated in labeling so that the healthcare provider can take this information into consideration, while making treatment decisions. Therefore, the table in the Clinical Studies section of the labeling will present the comparative study results from patients with meropenem- susceptible A. baumannii complex at baseline. The secondary endpoints of the APEKS-NP trial were clinical and microbiological outcomes at TOC and other timepoints (EA, EOT, and FU) by baseline pathogen. The clinical cure rates and microbiological eradication rates are shown in Table 19. Microbiological eradication at TOC 33 Integrated Review Template, version date 2019/10/16

Reference ID: 4676324 NDA 209445 / S-002 Cefiderocol (Fetroja) with cefiderocol was 45.8% (22/48) for K. pneumoniae, 37.5% (9/24) for P. aeruginosa, 39.1% (9/23) for A. baumannii, and 52.6% (10/19) for E. coli. For meropenem, these values were 54.5% (24/44), 45.8% (11/24), 33.3% (8/24), and 50.0% (11/22), respectively. Microbiological eradication and clinical cure rates at TOC were generally similar with cefiderocol and high- dose/extended-infusion meropenem for the five most common baseline pathogens (K. pneumoniae, P. aeruginosa, A. baumannii, E. coli, and E. cloacae). However, meropenem is not indicated for HABP/VABP and Acinetobacter, S. maltophilia, B. cepacia. There are limited data (<10 subjects with microbiological and clinical outcome) on HABP/VABP subjects with the following baseline pathogens: B. cepacia complex, Citrobacter koseri, E. cloacae complex, Klebsiella aerogenes, Klebsiella oxytoca, Proteus mirabilis, S. marcescens, and S. maltophilia. However, based on available data and similarity in clinical outcomes of subjects with E. cloacae complex and S. marcescens to the subjects with pathogens from the order Enterobacterales, E. cloacae complex and S. marcescens were included in the indication and List 1.

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Table 19. Summary of Clinical Cure and Microbiological Eradication Per Baseline Pathogen by Time Point -Modified Intention-to-Treat Population EA EOT TOC FU Sustained Sustained Clinical Micro Clinical Micro Clinical Micro Clinical Micro Pathogen Cure Eradication Cure Eradication Cure Eradication Cure Eradication Cefiderocol K. pneumoniae (n=48) 41 (85.4) 19 (39.6) 38 (79.2) 28 (58.3) 31 (64.6) 22 (45.8) 27 (56.3) 19 (39.6) P. aeruginosa (n=24) 20 (83.3) 8 (33.3) 22 (91.7) 17 (70.8) 16 (66.7) 9 (37.5) 14 (58.3) 10 (41.7) A. baumannii (n=23) 19 (82.6) 11 (47.8) 15 (65.2) 14 (60.9) 12 (52.2) 9 (39.1) 10 (43.5) 7 (30.4) E. coli (n=19) 16 (84.2) 8 (42.1) 15 (78.9) 12 (63.2) 12 (63.2) 10 (52.6) 12 (63.2) 9 (47.4) S. marcescens (n=8) 7 (87.5) 3 (37.5) 6 (75.0) 5 (62.5) 5 (62.5) 4 (50.0) 5 (62.5) 4 (50.0) E. cloacae (n=7) 7 (100.0) 4 (57.1) 5 (71.4) 4 (57.1) 5 (71.4) 4 (57.1) 5 (71.4) 3 (42.9) E. aerogenes (n=4) 1 (25.0) 1 (25.0) 2 (50.0) 2 (50.0) 1 (25.0) 1 (25.0) 1 (25.0) 1 (25.0) H. influenzae (n=3) 3 (100.0) 3 (100.0) 3 (100.0) 2 (66.7) 2 (66.7) 2 (66.7) 2 (66.7) 2 (66.7) M. catarrhalis (n=3) 3 (100.0) 2 (66.7) 3 (100.0) 3 (100.0) 3 (100.0) 2 (66.7) 3 (100.0) 1 (33.3) P. mirabilis (n=2) 2 (100.0) 2 (100.0) 2 (100.0) 2 (100.0) 1 (50.0) 1 (50.0) 1 (50.0) 1 (50.0) K. oxycota (n=2) 2 (100.0) 1 (50.0) 1 (50.0) 2 (100.0) 1 (50.0) 1 (50.0) 1 (50.0) 1 (50.0) A. nosocomialis (n=2) 1 (50.0) 2 (100.0) 1 (50.0) 1 (50.0) 1 (50.0) 1 (50.0) 1 (50.0) 1 (50.0) E. asburiae (n=2) 0 2 (100.0) 0 0 0 0 0 0 S. maltophilia (n=1) 1 (100.0) 1 (100.0) 1 (100.0) 1 (100.0) 1 (100.0) 1 (100.0) 1 (100.0) 1 (100.0) C. koseri (n=1) 1 (100.0) 1 (100.0) 1 (100.0) 1 (100.0) 1 (100.0) 1 (100.0) 1 (100.0) 1 (100.0) M. morganii (n=1) 0 1 (100.0) 0 0 0 0 0 0 C. freundii (n=1) 0 0 0 0 0 0 0 0 A. pittii (n=1) 0 1 (100.0) 0 1 (100.0) 1 (100.0) 1 (100.0) 0 1 (100.0) B. cepacia (n=1) 1 (100.0) 1 (100.0) 1 (100.0) 1 (100.0) 1 (100.0) 1 (100.0) 1 (100.0) 1 (100.0) H. parahaemolyticus (n=1) 1 (100.0) 1 (100.0) 1 (100.0) 1 (100.0) 1 (100.0) 1 (100.0) 1 (100.0) 1 (100.0)

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EA EOT TOC FU Sustained Sustained Clinical Micro Clinical Micro Clinical Micro Clinical Micro Pathogen Cure Eradication Cure Eradication Cure Eradication Cure Eradication Meropenem K. pneumoniae (n=44) 36 (81.8) 30 (68.2) 35 (79.5) 33 (75.0) 29 (65.9) 24 (54.5) 25 (56.8) 17 (38.6) P. aeruginosa (n=24) 20 (83.3) 11 (45.8) 19 (79.2) 16 (66.7) 17 (70.8) 11 (45.8) 13 (54.2) 10 (41.8) A. baumannii (n=24) 17 (70.8) 9 (37.5) 19 (79.2) 11 (45.8) 14 (58.3) 8 (33.3) 13 (54.2) 7 (20.2) E. coli (n=22) 20 (90.9) 11 (50.0) 19 (86.4) 16 (72.7) 13 (59.1) 11(50.0) 11 (50.0) 9 (40.9) S. marcescens (n=4) 3 (75.0) 2 (50.0) 3 (75.0) 2 (50.0) 3 (75.0) 2 (50.0) 3 (75.0) 2 (50.0) E. cloacae (n=8) 5 (62.5) 6 (75.0) 7 (87.5) 8 (100.0) 4 (50.0) 3 (37.5) 4 (50.0) 3 (37.5) E. aerogenes (n=1) 1 (100.0) 1 (100.0) 1 (100.0) 1 (100.0) 1 (100.0) 1 (100.0) 1 (100.0) 1 (100.0) H. influenzae (n=5) 5 (100.0) 4 (80.0) 5 (100.0) 5 (100.0) 4 (80.0) 4 (80.0) 4 (80.0) 2 (40.0) M. catarrhalis (n=2) 2 (100.0) 2 (100.0) 2 (100.0) 2 (100.0) 2 (100.0) 2 (100.0) 2 (100.0) 0 P. mirabilis (n=6) 5 (83.3) 3 (50.0) 4 (66.7) 4 (66.7) 2 (33.3) 1 (16.7) 2 (33.3) 1 (16.7) K. oxycota (n=3) 3 (100.0) 3 (100.0) 2(66.7) 3 (100.0) 2(66.7) 2(66.7) 1 (33.3) 2(66.7) A. nosocomialis (n=1) 0 0 1 (100.0) 1 (100.0) 1 (100.0) 1 (100.0) 0 0 E. asburiae (n=1) 1 (100.0) 1 (100.0) 1 (100.0) 0 1 (100.0) 1 (100.0) 1 (100.0) 1 (100.0) S. maltophilia (n=3) 2 (66.7) 1 (33.3) 2 (66.7) 2 (66.7) 2 (66.7) 1 (33.3) 2 (66.7) 1 (33.3) C. koseri (n=2) 2 (100.0) 1 (50.0) 2 (100.0) 2 (100.0) 2 (100.0) 2 (100.0) 2 (100.0) 2 (100.0) M. morganii (n=2) 1 (50.0) 2 (100.0) 2 (100.0) 2 (100.0) 0 0 0 0 C. freundii (n=1) 1 (100.0) 0 1 (100.0) 0 1 (100.0) 1 (100.0) 1 (100.0) 1 (100.0) A. pittii (n=0) 0 0 0 0 0 0 0 0 B. cepacia (n=0) 0 0 0 0 0 0 0 0 H. parahaemolyticus (n=0) 0 0 0 0 0 0 0 0 Source: Table 14.2.8.1.1 and Table 14.2.9.1.1 All values are presented as n (%) Abbreviations: EA, early assessment; EOT, end of therapy; FU, follow-up; TOC, test-of-cure

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Reference ID: 4676324 NDA 209445 / S-002 Cefiderocol (Fetroja)

6.4.4. Important Review Issue #4 Relevant to Benefit Issue Revisit breakpoints established by FDA for Enterobacteriaceae and P. aeruginosa and establishbreakpoints for A. baumannii complex. The currently approved FDA breakpoints are shown in Table 20.

Table 20. FDA-Identified Breakpoints MIC Disk Diffusion (mcg/mL) (Sone Diameters in mm) Pathogen S I R S I R Enterobacteriaceaea ≤2 4 ≥8 ≥18 14–17 ≤13 Pseudomonas aeruginosa ≤1 2 ≥4 ≥25 19–24 ≤18 Source: https://www.fda.gov/drugs/development-resources/cefiderocol-injection a Includes E. coli, K. pneumoniae, P. mirabilis, and E. cloacae complex. For disk diffusion, use paper disks impregnated with 30 mcg cefiderocol. Abbreviations: I, intermediate; MIC, minimum inhibitory concentration; R, resistant; S, Susceptible These breakpoints were established by taking into account the cefiderocol MIC distribution in surveillance and clinical studies, cefiderocol MIC90 values in surveillance studies, clinical cure rates by MIC of the baseline pathogen in the cUTI study, and pharmacokinetic- pharmacodynamic (PK-PD) target attainment analyses. The Applicant’s proposed breakpoints are shown in Table 21. These breakpoints rely heavily on the animal data using simulated human dosing for PK/PD assessments to bridge the gap between data from surveillance and clinical studies and on the cefiderocol MIC90 values for carbapenem-resistant pathogens. These breakpoints were also tentatively proposed by the Clinical and Laboratory Standards Institute (CLSI) based on animal data.

Table 21. Applicant’s Proposed Breakpoints

Source: Table 7 in section 2.7.2.4.Addendum-HABP/VABP of the Application Abbreviations: I, intermediate; MIC, minimum inhibitory concentration; R, resistant; S, susceptible

The cefiderocol MIC90 values against Enterobacterales, P. aeruginosa, and A. baumannii complex in surveillance studies and the cefiderocol MIC90 values against meropenem-resistant Enterobacterales, P. aeruginosa, and A. baumannii complex using the updated surveillance study data are the same as those in the original NDA. For the APEKS-NP study, the clinical cure rates and microbiological eradication rates for subjects with baseline Enterobacterales at the cefiderocol MIC of 2 mcg/mL were 70% (7/10) and 40% (4/10), respectively. There are very limited data at MIC of 4 mcg/mL (clinical cure rate 50% (1/2) and no microbiological eradication). However, four subjects in the cUTI trial had isolates with cefiderocol MIC of 4 37 Integrated Review Template, version date 2019/10/16

Reference ID: 4676324 NDA 209445 / S-002 Cefiderocol (Fetroja) mcg/mL. All four subjects were clinically cured, and three out of the four subjects showed microbiological eradication. In the case of P. aeruginosa, the cefiderocol MIC for the clinical isolates ranged from ≤0.03 to 1 mcg/mL (MIC90=0.5 mcg/mL). There were two subjects with isolates at an MIC of 1 mcg/mL, and both were clinically cured with microbiological eradication in one subject. There were no data above an MIC of 1 mcg/mL. The Applicant stated that in addition to the APEKS-NP data, five subjects in the compassionate use program (three with cefiderocol MIC of 2 mcg/mL and two with cefiderocol MIC of 4 mcg/mL) responded to cefiderocol treatment. However, the compassionate use data were not considered in the assessment due to the open-label and uncontrolled nature of the data. In the case of A. baumannii, the cefiderocol MIC for the clinical isolates ranged from ≤0.03 to >64 mcg/mL (MIC90=2 mcg/mL). The cefiderocol MIC90 for A. baumannii complex in surveillance studies was 2 mcg/mL. There were two subjects with isolates at an MIC of 1 mcg/mL and both had a clinical cure with microbiological eradication in one subject. At an MIC of 2 mcg/ml, the clinical cure and microbiological eradication rates were 33.3% (1/3). The combined data from the cUTI and HABP/VABP clinical studies support a change in MIC breakpoints for Enterobacterales but not P. aeruginosa. The cefiderocol susceptible breakpoint for A. baumannii can be set at ≤1 mcg/mL based on limited clinical data. The resistant breakpoint is set at ≥ 4 mcg/mL. No breakpoints are proposed for S. maltophilia as it is not indicated for HABP/VABP. The revised FDA identified breakpoints are shown in Table 22.

Table 22. Revised FDA Identified Breakpoints Minimum Inhibitory Disk Diffusion (zone Concentrations diameters in mm) (mcg/mL)

Pathogen S I R S I R

Enterobacteralesa,b ≤4 8 ≥ 16 ≥16 9-15 ≤8

Pseudomonas aeruginosa ≤1 2 ≥ 4 ≥22 13-21 ≤12

Acinetobacter baumannii ≤1 2 ≥ 4 ≥19 12-18 ≤11 complex

aClinical efficacy was shown for Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, and Enterobacter cloacae complex in patients with complicated urinary tract infections (cUTI). bClinical efficacy was shown for Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae complex, and Serratia marcescens in patients with hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (HABP/VABP) . S = Susceptible; I = Intermediate; R = Resistant For disk diffusion, use paper disks impregnated with 30 mcg cefiderocol.

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Reference ID: 4676324 NDA 209445 / S-002 Cefiderocol (Fetroja) 7. Risk and Risk Management 7.1. Potential Risks or Safety Concerns Based on Nonclinical Data No new safety concerns based on nonclinical data have been found. See review of NDA 209445 (Division of Anti-Infectives 2019) for information noted previously. 7.2. Potential Risks or Safety Concerns Based on Drug Class or Other Drug-Specific Factors Potential risks based on β-lactam antibacterial class effects include rash/hypersensitivity reactions, Clostridioides difficile-associated diarrhea, hepatotoxicity, seizures and other central nervous system abnormalities, renal toxicity, and hematologic reactions (immune-mediated hemolytic anemia, hypothrombinemia). Additional safety concerns include other hematologic risks such as anemia, bleeding, coagulopathy, and thrombosis due to the iron-based mechanism of entry. Patients with TEAEs related these antibacterial class effects are noted in Section 7.6.5. 7.3. Potential Safety Concerns Identified Through Postmarket Experience A search of the FDA Adverse Event Reporting System database yielded eight postmarketing reports of TEAEs associated with the use of cefiderocol. Five cases were from the United States, and the remaining were from foreign countries. Two resulted in death, one was life-threatening, and three had other outcomes. The individual preferred terms (PTs) were pyrexia (possible drug fever), PR prolongation and extrasystoles, cardiac arrest, seizure, chromaturia (asymptomatic blue to purplish discoloration of the urine), sepsis and multiple organ dysfunction syndrome (MODS) in two patients (both resulting in death), and acute kidney injury (AKI). In addition, there have been two 15-day safety reports of AKI due to suspected allergic interstitial nephritis associated with cefiderocol; one was submitted on June 10, 2019, prior to approval, and one was submitted on April 9, 2020. In both cases, peripheral eosinophilia occurred with a decline in renal function while on cefiderocol, but a renal biopsy was not performed for confirmatory evidence. In the first report, aztreonam was given concomitantly; however, the physician suspected cefiderocol rather than aztreonam due to timing of administration. Other confounders included colistin given for an unknown duration and a possible concomitant UTI. In the second report, there was no other confounding medication except for paracetamol, and the event of AKI was noted to be possibly related by the investigator. Confounders also included underhydration. There were two cardiac events reported. One patient with a history of coronavirus disease 2019 (COVID-19) about 2 months prior to receiving cefiderocol developed PR prolongation with frequent extrasystoles. The PR prolongation resolved after discontinuation of cefiderocol and the investigator causality was related. Another patient with a history of ongoing COVID-19 pneumonia (onset unknown) developed cardiac arrest 2 days after receiving cefiderocol leading to treatment discontinuation. The investigator causality was related, and potential confounders were furosemide, propofol, and fentanyl.

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Reference ID: 4676324 NDA 209445 / S-002 Cefiderocol (Fetroja) Seizure occurred in one patient with no prior seizure history who was receiving CRRT for AKI. The seizure occurred 13 days after cefiderocol was started, leading to treatment discontinuation. Seizure is noted as a warning in cefiderocol labeling. In addition, a 7-day report was submitted on January 13, 2020, for a patient who had developed mucormycosis requiring withdrawal of cefiderocol with an outcome of not recovered. The patient was an 18-year-old female with a history of cystic fibrosis who was treated with cefiderocol for Achromobacter xylosoxidans and Haemophilus influenzae pneumonia, and multiorgan dysfunction requiring extracorporeal membrane oxygenation (ECMO) in the compassionate use program. She also developed A. xylosoxidans bacteremia. She underwent left femoral artery ECMO decannulation with angioplasty with greater saphenous vein patch and lower extremity fasciotomy due to acute limb ischemia associated with common femoral artery thrombosis. The fasciotomy site grew a Mucor species for which she was given amphotericin. The attending physician discontinued cefiderocol due to the concern that cefiderocol may have acted as a xenosiderophore and promoted infection with Mucor species by increasing available free iron. Other risk factors for development of Mucor species included neutropenia, hyperglycemia, ischemic injury from ECMO and fasciotomy, steroids, and blood transfusion. 7.4. FDA Approach to the Safety Review Data from the APEKS-NP trial is the focus of the safety review. Although the CREDIBLE-CR trial included subjects with NP, the data was not pooled for safety assessments given differences in study design and populations. The available data from the CREDIBLE-CR trial was assessed during the original NDA review, and the clinical study report submitted with this sNDA contains the same information as was previously reviewed. See original NDA for the review of the CREDIBLE-CR trial. 7.5. Adequacy of the Clinical Safety Database The dosing, duration, and number of subjects in the safety database are sufficient to conduct a safety review for the HABP/VABP indication. A total of 97 of 148 (65.5%) patients in the cefiderocol arm and 110 of 150 (73.3%) patients in the meropenem arm received between 7 and 14 days of therapy, which is the proposed duration of treatment for the indication sought. Of note, more patients in the cefiderocol arm had a longer exposure to treatment (>14 days) than in the meropenem group. Per protocol, treatment duration may have been extended up to 21 days based on the investigator’s clinical assessment of the patients. Two subjects in the cefiderocol group and one subject in the meropenem group were shown as having 22 days of exposure to study treatment due to how their infusion start and end times fell on calendar days. However, actual administration duration was 21 days for each of these three subjects.

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Table 23. Duration of Exposure, Safety Population, APEKS-NP Trial Cefiderocol Meropenem Total Variable N=148 N=150 N=298 Duration of treatment (days) Mean (SD) 10.4 (4.1) 10.1 (4.0) 10.3 (4.1) Median (min, max) 10.0 (2.0, 22.0) 8.5 (1.0, 22.0) 9.0 (1.0, 22.0) Subjects treated, by duration, n (%) <7 days 18 (12.2) 15 (10.0) 33 (11.1) 7 to 14 days 97 (65.5) 110 (73.3) 207 (69.5) >14 to 20 days 31 (20.9) 24 (16.0) 55 (18.5) >21 days 2 (1.4) 1 (0.7) 3 (1.0) Source: adex.xpt; Software: Python Abbreviations: N, number of subjects in treatment arm; n, number of subjects with given treatment duration; SD, standard deviation 7.6. Safety Findings and Safety Concerns Based on Review of the Clinical Safety Database 7.6.1. Overall Adverse Event Summary An overall summary of TEAEs is presented in Table 24. While TEAEs occurred at a similar frequency in both treatment groups, moderate or severe TEAEs and serious AEs (SAEs) with or without a fatal outcome occurred more frequently in the cefiderocol group (≥3%) than they did in the meropenem group. TEAEs leading to discontinuation of the study drug occurred at a similar frequency in both treatment groups. The TEAEs leading to interruption of the study drug in the cefiderocol group were cardiac arrest and cardiac failure (one patient each, both considered not related to study drug per the investigator and with fatal outcomes); and ear discomfort and headache (one patient, considered related to study drug per the investigator with outcome ‘resolved’). In the meropenem group, TEAEs leading to interruption of study drug were hemorrhagic shock (with a fatal outcome), renal impairment (outcome not resolved), and anuria (outcome not resolved). The TEAEs occurred in one patient each and were all considered not related per the investigator.

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Table 24. Overview of Treatment-Emergent Adverse Events, Safety Population, APEKS-NP Trial Cefiderocol Meropenem Total Risk Event Category N=148 N=150 N=298 Difference Any TEAE 130 (87.8) 129 (86.0) 259 (86.9) 1.8 (-5.8, 9.5) Moderate or severe TEAEs 97 (65.5) 92 (61.3) 189 (63.4) 4.2 (-6.7, 15.1) Any SAE 54 (36.5) 45 (30.0) 99 (33.2) 6.5 (-4.2, 17.2) SAE with fatal outcome 39 (26.4) 35 (23.3) 74 (24.8) 3.1 (-6.7, 12.9) TEAE leading to discontinuation of study drug 12 (8.1) 14 (9.3) 26 (8.7) -1.2 (-7.6, 5.2) TEAE leading to dose modification of study drug 3 (2.0) 3 (2.0) 6 (2.0) 0.0 (-3.2, 3.2) TEAE leading to interruption of study drug 3 (2.0) 1 (0.7) 4 (1.3) 1.3 (-1.3, 3.9) TEAE leading to reduction of study drug 0 2 (1.3) 2 (0.7) -1.3 (-3.2, 0.5) TEAE leading to delay of study drug 0 0 0 0.0 (0.0, 0.0) Source: adae.xpt; Software: Python All values are expressed as n (%) except those in the Risk Difference column. The Risk Difference column shows absolute difference (with 95% confidence interval) between cefiderocol and meropenem. Treatment-emergent adverse events are defined as adverse events that started after the initial dose of study treatment or comparator and up to the EOS The severity of an event was graded by the investigator or subinvestigator according to the following definitions: Mild: A finding or symptom is minor and does not interfere with usual daily activities; Moderate: The event causes discomfort and interferes with usual daily activity or affects clinical status; Severe: The event causes interruption of the subject’s usual daily activities or has a clinically significant effect Abbreviations: CI, confidence interval; EOS, end of study; N, number of subjects in treatment arm; n, number of subjects with at least one event; SAE, serious adverse event; TEAE, treatment-emergent adverse event 7.6.2. Deaths In the safety population (n=298), there were 74 treatment-emergent deaths, i.e., 74 patients died (b) (6) on or before the EOS, including one subject ( ), who had an ongoing SAE at the EOS visit and died the next day. TEAEs leading to death occurred in 26.4% (39/148) in the cefiderocol group and 23.3% (35/150) in the meropenem group (a risk difference of 3.0%). In addition, there were eight patients (three in the cefiderocol group and five in the meropenem group) who were reported as having died after the EOS through spontaneous reporting such as in response to an Electronic Data Capture query or in a FU liver event form. None of the deaths in either treatment group were considered related to study treatment by either the sponsor or investigator. However, TEAEs leading to death were reported for one patient (sepsis secondary to HABP) in the cefiderocol group and two patients (Pseudomonas infection in one patient; disseminated intravascular coagulation and MODS, both related to a concomitant medication [linezolid]) in one patient in the meropenem group. Most often, the deaths occurred as a result of the underlying comorbidities and concurrent illness in this severely ill population with NP and were relatively similar between treatment groups. As the labeling for cefiderocol includes a mortality warning in patients with NP based on the results of the mortality imbalance in the CREDIBLE-CR trial, a detailed mortality analysis was performed for the APEKS-NP trial, and results are noted in Section 7.7.1. 7.6.3. Serious Adverse Events SAEs occurred at a slightly higher frequency in the cefiderocol group, with a risk difference of 6.5%. The following table lists SAEs by system organ class (SOC). The SOCs with at least a 1% higher frequency of SAEs in the cefiderocol group were infections and infestations, respiratory, thoracic, and mediastinal and gastrointestinal (GI) disorders. The SAEs were further evaluated with the currently available FDA Medical Dictionary for Regulatory Activities Queries (FMQs)

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Reference ID: 4676324 NDA 209445 / S-002 Cefiderocol (Fetroja) as noted in Table 26. Of note, FMQs are currently in development and a complete listing of FMQs are not available at the time of this review [e.g., an FMQ related to cerebrovascular accident (CVA) has not yet been developed]. Pneumonia in the infections and infestations SOC and acute coronary syndrome in the cardiac disorders SOC were reported in a greater number of patients in the cefiderocol group. As grouped queries for all pneumonia-related TEAEs yielded even higher numbers of patients with pneumonia in both treatment groups, these were analyzed further and are discussed in Section 7.6.5. Other infectious and cardiac events are also discussed in this section. SAEs by other FMQs did not raise safety concerns. Per the investigator, there were three patients in the cefiderocol group and five in the meropenem group with treatment-related SAEs. In the cefiderocol group, two patients had elevated liver tests which resolved and one patient had acute respiratory failure, pleural effusion, and sepsis secondary to HABP, which led to death. In the meropenem group, three subjects had treatment- related SAEs that were considered related to linezolid or other concomitant therapy (i.e., red blood cell transfusion). One patient had an SAE of Pseudomonas infection and hemorrhagic shock that led to death, and one patient had elevated liver tests that did not resolve by the EOS. Additional SAEs in which contribution of cefiderocol could not be excluded are noted below. An additional five SAEs in the cefiderocol group appeared to be related to elevated liver tests. Case summaries for hepatic TEAEs are noted in Section 7.6.5. (b) (6) • – Coagulopathy. 79-year-old male with hypertension (HTN) and DM with a baseline international normalized ratio (INR, normal range 0.8 to 1.2) of 1.5 and activated partial thromboplastin time (aPTT, normal range 25 to 43 seconds) of 28.2 seconds developed nonserious coagulopathy on day 5 with a prothrombin time of 29.1 seconds (normal range not provided) and aPTT >150 seconds. He had been receiving enoxaparin from day -9 until day 7. Cefiderocol was given until day 14. An SAE of coagulopathy occurred on day 12 (prothrombin time: 29 seconds, INR 2.2, aPTT 47.4 seconds). No bleeding events were reported. It cannot be fully excluded that cefiderocol increased the coagulation parameters, even after confounding medication (enoxaparin) was discontinued. He died due to cardiac arrest on day 14. (b) (6) • – Thrombocytopenia. 75-year-old female with CKD, DM, and HTN developed thrombocytopenia from days 15 to 25. The baseline platelet count was 394×109/L (normal range 150 to 450) and decreased to 78×109/L on day 22. Cefiderocol was discontinued on day 16. The platelet count recovered to 585×109/L by day 27. No bleeding events were noted, but hematology was consulted and did not recommend medical intervention. It cannot be fully excluded that cefiderocol contributed to thrombocytopenia. (b) (6) • – Stridor. 55-year-old female with asthma, chronic obstructive pulmonary disease (COPD), and depression developed a TEAE of HTN on day 7, which did not resolve. She developed dermatitis, which was treated with chloropyramine on day 20 and was resolved by day 26. Cefiderocol was discontinued on day 8. Whether events between the onsets of dermatitis and stridor occurred is unknown. On day 36, she developed an SAE of stridor for which she underwent balloon dilatation. No other etiology of stridor was given. However, due to the delayed onset of stridor (28 days after study drug discontinuation), causality to cefiderocol is less likely. 43 Integrated Review Template, version date 2019/10/16

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(b) (6) – Status epilepticus. 26-year-old male with chronic kidney disease (CKD) on hemodialysis, HTN, and history of typhoid fever developed hypocalcemia on day 3. The serum calcium was 1.7 mmol/L at baseline (normal range 2.12 to 2.5) and decreased to 1.3 mmol/mL on day 3. Hypocalcemia resolved on day 39 after treatment with calcium carbonate from days 12 to 27. Cefiderocol was discontinued on day 11. He also had TEAEs of coronary artery disease (CAD) and congestive heart failure (CHF). On day 33, he developed SAEs of acute respiratory failure, cardiorespiratory arrest, left ventricular dysfunction, and status epilepticus, for which he was given antiseizure medication. It cannot be fully excluded that cefiderocol contributed to hypocalcemia, hypocalcemia- triggered status epilepticus, or status epilepticus alone given risk for seizures with use of cefiderocol.

Table 25. Serious Adverse Events by System Organ Class and Preferred Term, Safety Population, APEKS-NP Trial System Organ Class Cefiderocol Meropenem Total Preferred Term N=148 N=150 N=298 Risk Difference Any SAE 54 (36.5) 45 (30.0) 99 (33.2) 6.5 (-4.2, 17.2) Infections and infestations 17 (11.5) 14 (9.3) 31 (10.4) 2.2 (-4.8, 9.1) Pneumonia 6 (4.1) 3 (2.0) 9 (3.0) 2.1 (-1.8, 5.9) Septic shock 4 (2.7) 1 (0.7) 5 (1.7) 2.0 (-0.9, 5.0) Sepsis 3 (2.0) 2 (1.3) 5 (1.7) 0.7 (-2.2, 3.6) Bacteremia 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Bacterial sepsis 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Herpes zoster 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Lung infection 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Pneumonia bacterial 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Spinal cord infection 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Urinary tract infection 1 (0.7) 2 (1.3) 3 (1.0) -0.6 (-2.9, 1.7) Acinetobacter bacteremia 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Brain abscess 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Meningitis 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Meningoencephalitis bacterial 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Pneumonia necrotising 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Pseudomonas infection 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Septic encephalopathy 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Systemic candida 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Respiratory, thoracic and mediastinal disorders 17 (11.5) 15 (10.0) 32 (10.7) 1.5 (-5.5, 8.5) Acute respiratory failure 6 (4.1) 1 (0.7) 7 (2.3) 3.4 (-0.0, 6.8) Pulmonary edema 2 (1.4) 0 2 (0.7) 1.4 (-0.5, 3.2) Pneumonia aspiration 3 (2.0) 2 (1.3) 5 (1.7) 0.7 (-2.2, 3.6) Acute respiratory distress syndrome 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Pneumothorax spontaneous 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Pulmonary hypertension 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Stridor 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Pulmonary artery thrombosis 3 (2.0) 3 (2.0) 6 (2.0) 0.0 (-3.2, 3.2) Pleural effusion 1 (0.7) 1 (0.7) 2 (0.7) 0.0 (-1.8, 1.9) Pulmonary embolism 1 (0.7) 1 (0.7) 2 (0.7) 0.0 (-1.8, 1.9) Respiratory failure 2 (1.4) 3 (2.0) 5 (1.7) -0.6 (-3.6, 2.3) Bronchopleural fistula 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Chronic obstructive pulmonary disease 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Pneumothorax 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Pulmonary congestion 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Respiratory distress 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) 44 Integrated Review Template, version date 2019/10/16

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System Organ Class Cefiderocol Meropenem Total Preferred Term N=148 N=150 N=298 Risk Difference Gastrointestinal disorders 4 (2.7) 2 (1.3) 6 (2.0) 1.4 (-1.8, 4.6) Abdominal wall hematoma 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Gastric hemorrhage 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Intestinal infarction 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Intestinal ischemia 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Acute abdomen 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Gastrointestinal hemorrhage 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Cardiac disorders 16 (10.8) 15 (10.0) 31 (10.4) 0.8 (-6.1, 7.7) Cardiac arrest 7 (4.7) 5 (3.3) 12 (4.0) 1.4 (-3.1, 5.9) Acute myocardial infarction 2 (1.4) 0 2 (0.7) 1.4 (-0.5, 3.2) Left ventricular dysfunction 2 (1.4) 0 2 (0.7) 1.4 (-0.5, 3.2) Cardio-respiratory arrest 3 (2.0) 2 (1.3) 5 (1.7) 0.7 (-2.2, 3.6) Myocardial infarction 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Cardiovascular insufficiency 1 (0.7) 1 (0.7) 2 (0.7) 0.0 (-1.8, 1.9) Cardiac failure 2 (1.4) 3 (2.0) 5 (1.7) -0.6 (-3.6, 2.3) Cardiac failure congestive 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Cardiogenic shock 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Cardiopulmonary failure 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Cardiovascular disorder 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Cardiac failure acute 0 2 (1.3) 2 (0.7) -1.3 (-3.2, 0.5) General disorders and administration site 7 (4.7) 6 (4.0) 13 (4.4) 0.7 (-3.9, 5.4) conditions General physical health deterioration 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Sudden death 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Multiple organ dysfunction syndrome 4 (2.7) 4 (2.7) 8 (2.7) 0.0 (-3.6, 3.7) Death 1 (0.7) 1 (0.7) 2 (0.7) 0.0 (-1.8, 1.9) SIRS 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Neoplasms benign, malignant and 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) unspecified (incl cysts and polyps) Lung cancer metastatic 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Skin and subcutaneous tissue disorders 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Diabetic foot 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Surgical and medical procedures 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Leg amputation 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Injury, poisoning and procedural 1 (0.7) 1 (0.7) 2 (0.7) 0.0 (-1.8, 1.9) complications Subarachnoid hemorrhage 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Splenic rupture 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Hepatobiliary disorders 1 (0.7) 2 (1.3) 3 (1.0) -0.6 (-2.9, 1.7) Hepatocellular injury 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Cholecystitis acute 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Hepatic function abnormal 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Metabolism and nutrition disorder 1 (0.7) 2 (1.3) 3 (1.0) -0.6 (-2.9, 1.7) Lactic acidosis 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Hyperkalemia 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Hypovolemia 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6)

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System Organ Class Cefiderocol Meropenem Total Preferred Term N=148 N=150 N=298 Risk Difference Nervous system disorders 9 (6.1) 11 (7.3) 20 (6.7) -1.2 (-6.9, 4.5) Cerebrovascular accident 2 (1.4) 1 (0.7) 3 (1.0) 0.7 (-1.6, 3.0) Intracranial pressure increased 2 (1.4) 1 (0.7) 3 (1.0) 0.7 (-1.6, 3.0) Autonomic nervous system imbalance 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Cerebral ischemia 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Hypoxic-ischemic encephalopathy 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Status epilepticus 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Stroke in evolution 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Metabolic encephalopathy 1 (0.7) 1 (0.7) 2 (0.7) 0.0 (-1.8, 1.9) Brain injury 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Encephalopathy 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Lacunar stroke 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Brain edema 1 (0.7) 5 (3.3) 6 (2.0) -2.6 (-5.8, 0.6) Investigations 6 (4.1) 8 (5.3) 14 (4.7) -1.2 (-6.0, 3.6) Liver function test increased 2 (1.4) 0 2 (0.7) 1.4 (-0.5, 3.2) Alanine aminotransferase increased 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Blood pressure increased 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Aspartate aminotransferase increased 1 (0.7) 1 (0.7) 2 (0.7) 0.0 (-1.8, 1.9) Transaminases increased 1 (0.7) 1 (0.7) 2 (0.7) 0.0 (-1.8, 1.9) Liver function test abnormal 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Hepatic enzyme increased 1 (0.7) 5 (3.3) 6 (2.0) -2.6 (-5.8, 0.6) Renal and urinary disorders 1 (0.7) 3 (2.0) 4 (1.3) -1.3 (-3.9, 1.3) Acute kidney injury 1 (0.7) 3 (2.0) 4 (1.3) -1.3 (-3.9, 1.3) Vascular disorders 1 (0.7) 3 (2.0) 4 (1.3) -1.3 (-3.9, 1.3) Peripheral vascular disorder 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Femoral artery embolism 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Hypotension 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Hypovolemic shock 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Shock hemorrhagic 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Blood and lymphatic system disorders 2 (1.4) 6 (4.0) 8 (2.7) -2.6 (-6.3, 1.0) Coagulopathy 1 (0.7) 2 (1.3) 3 (1.0) -0.6 (-2.9, 1.7) Thrombocytopenia 1 (0.7) 2 (1.3) 3 (1.0) -0.6 (-2.9, 1.7) Disseminated intravascular coagulation 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Hemorrhagic anemia 0 2 (1.3) 2 (0.7) -1.3 (-3.2, 0.5) Source: adae.xpt; Software: Python All values are expressed as n (%) except those in the Risk Difference column. The Risk Difference column shows absolute difference (with 95% confidence interval) between cefiderocol and meropenem. Treatment-emergent adverse are defined as the severity of an event was graded by the investigator or subinvestigator according to the following definitions: Mild: A finding or symptom is minor and does not interfere with usual daily activities; Moderate: The event causes discomfort and interferes Abbreviations: CI, confidence interval; N, number of subjects in treatment arm; n, number of subjects with adverse event; SAE, serious adverse event; SIRS, systemic inflammatory response syndrome

Table 26. Serious Adverse Events by FDA MedDRA Query (Narrow), Safety Population, APEKS-NP Trial FMQ (Narrow) Cefiderocol Meropenem Total Preferred Term N=148 N=150 N=298 Risk Difference Pneumonia 10 (6.8) 6 (4.0) 16 (5.4) 2.8 (-2.4, 7.9) Pneumonia 6 (4.1) 3 (2.0) 9 (3.0) 2.1 (-1.8, 5.9) Pneumonia aspiration 3 (2.0) 2 (1.3) 5 (1.7) 0.7 (-2.2, 3.6) Lung infection 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Pneumonia bacterial 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Pneumonia necrotising 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6)

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FMQ (Narrow) Cefiderocol Meropenem Total Preferred Term N=148 N=150 N=298 Risk Difference Acute coronary syndrome 3 (2.0) 0 3 (1.0) 2.0 (-0.2, 4.3) Acute myocardial infarction 2 (1.4) 0 2 (0.7) 1.4 (-0.5, 3.2) Myocardial infarction 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Systemic hypertension 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Blood pressure increased 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Malignancy 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Lung cancer metastatic 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Seizure 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Status epilepticus 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Hepatic injury 2 (1.4) 2 (1.3) 4 (1.3) 0.1 (-2.5, 2.7) Alanine aminotransferase increased 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Hepatocellular injury 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Aspartate aminotransferase increased 1 (0.7) 1 (0.7) 2 (0.7) 0.0 (-1.8, 1.9) Hepatic function abnormal 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Hemorrhage 3 (2.0) 3 (2.0) 6 (2.0) 0.0 (-3.2, 3.2) Abdominal wall hematoma 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Gastric hemorrhage 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Subarachnoid hemorrhage 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Gastrointestinal hemorrhage 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Shock hemorrhagic 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Hemorrhagic anemia 0 2 (1.3) 2 (0.7) -1.3 (-3.2, 0.5) Thrombocytopenia 1 (0.7) 2 (1.3) 3 (1.0) -0.6 (-2.9, 1.7) Thrombocytopenia 1 (0.7) 2 (1.3) 3 (1.0) -0.6 (-2.9, 1.7) Abdominal pain 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Acute abdomen 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Cholecystitis 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Cholecystitis acute 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Dyspnea 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Respiratory distress 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Hypotension 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Hypotension 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Acute kidney injury 1 (0.7) 3 (2.0) 4 (1.3) -1.3 (-3.9, 1.3) Acute kidney injury 1 (0.7) 3 (2.0) 4 (1.3) -1.3 (-3.9, 1.3) Anemia 0 2 (1.3) 2 (0.7) -1.3 (-3.2, 0.5) Hemorrhagic anemia 0 2 (1.3) 2 (0.7) -1.3 (-3.2, 0.5) Source: adae.xpt; Software: Python All values are expressed as n (%) except those in the Risk Difference column. The Risk Difference column shows absolute difference (with 95% confidence interval) between cefiderocol and meropenem. Treatment-emergent adverse events are defined as adverse events that started after the initial dose of study treatment or comparator and up to the EOS The severity of an event was graded by the investigator or subinvestigator according to the following definitions: Mild: A finding or symptom is minor and does not interfere with usual daily activities; Moderate: The event causes discomfort and interferes with usual daily activity or affects clinical Abbreviations: CI, confidence interval; EOS, end of study; FMQ, FDA medDRA query; N, number of subjects in treatment arm; n, number of subjects with adverse event 7.6.4. Dropouts and/or Discontinuations Due to Adverse Events Of all randomized patients in the trial, 28.4% (42/148) in the cefiderocol group and 26.3% (40/152) in the meropenem group discontinued the study. No patients in the cefiderocol group and one patient (471005) in the meropenem group discontinued the study, which was due to an SAE of abnormal hepatic function.

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Reference ID: 4676324 NDA 209445 / S-002 Cefiderocol (Fetroja) A similar number of patients in both treatment groups discontinued study treatment due to TEAEs, as noted in Table 27 below. A listing of each discontinuation and an assessment of relatedness to study drug by the investigator and reviewer is noted in Section 17, Table 69. The most common TEAE leading to discontinuation in both treatment groups involved hepatotoxicity (elevated liver tests). In the cefiderocol group, hepatic-related TEAEs that may have resulted in treatment discontinuation (reviewer assessment was ‘related’) included increases in aspartate aminotransferase (AST) increased, alanine aminotransferase (ALT) increased, and blood alkaline phosphatase (ALP) increased, abnormal liver function test (LFT) abnormal, increased LFT increased, and hepatic failure and in the meropenem group, hepatic-related TEAEs included increased hepatic enzyme increased. In the cefiderocol group, two additional TEAEs [(acute myocardial infarction ([MI]) and cerebrovascular accident (CVA)] may have resulted in treatment discontinuation. Also, in another patient, acute respiratory distress syndrome (ARDS), due to progression of the original NP may have resulted in treatment discontinuation and the need for rescue antibacterial drugs. In the meropenem group, systemic inflammatory response syndrome (SIRS), acute respiratory failure, and respiratory failure may have resulted in treatment discontinuation due to progression of the original NP. The other TEAEs leading to discontinuation appeared to be unrelated to treatment discontinuation.

Table 27. TEAEs by System Organ Class Leading to Discontinuation, Safety Population, APEKS- NP Trial System Organ Class Cefiderocol Meropenem Total Preferred Term N=148 N=150 N=298 Risk Difference Any TEAE leading to discontinuation 12 (8.1) 14 (9.3) 26 (8.7) -1.2 (-7.6, 5.2) Investigations 5 (3.4) 5 (3.3) 10 (3.4) 0.1 (-4.0, 4.2) Alanine aminotransferase increased 2 (1.4) 0 2 (0.7) 1.4 (-0.5, 3.2) Aspartate aminotransferase increased 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Blood alkaline phosphatase increased 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Liver function test abnormal 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Liver function test increased 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Hepatic enzyme increased 0 5 (3.3) 5 (1.7) -3.3 (-6.2, -0.5) Nervous system disorders 4 (2.7) 1 (0.7) 5 (1.7) 2.0 (-0.9, 5.0) Autonomic nervous system imbalance 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Cerebrovascular accident 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Stroke in evolution 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Brain oedema 1 (0.7) 1 (0.7) 2 (0.7) 0.0 (-1.8, 1.9) Hepatobiliary 2 (1.4) 1 (0.7) 3 (1.0) 0.7 (-1.6, 3.0) Hepatic failure 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Hepatocellular injury 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Hepatic function abnormal 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Gastrointestinal disorders 2 (1.4) 1 (0.7) 3 (1.0) 0.7 (-1.6, 3.0) Gastric hemorrhage 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Intestinal infarction 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Upper gastrointestinal hemorrhage 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Cardiac disorders 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Acute myocardial infarction 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Metabolism and nutrition disorders 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Lactic acidosis 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0)

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System Organ Class Cefiderocol Meropenem Total Preferred Term N=148 N=150 N=298 Risk Difference Respiratory, thoracic and mediastinal disorders 1 (0.7) 2 (1.3) 3 (1.0) -0.6 (-2.9, 1.7) Acute respiratory distress syndrome 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Acute respiratory failure 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Pulmonary congestion 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Respiratory failure 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Infections and infestations 1 (0.7) 4 (2.7) 5 (1.7) -2.0 (-4.9, 0.9) Septic shock 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Acinetobacter infection 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Meningitis bacterial 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Sepsis 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Urinary tract infection 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Blood and lymphatic system disorders 0 2 (1.3) 2 (0.7) -1.3 (-3.2, 0.5) Disseminated intravascular coagulation 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Leukopenia 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) General disorders and administration site 0 2 (1.3) 2 (0.7) -1.3 (-3.2, 0.5) conditions Multiple organ dysfunction syndrome 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Systemic inflammatory response 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) syndrome Source: adae.xpt; Software: Python All values are expressed as n (%) except those in the Risk Difference column. The Rsk Difference column shows absolute difference (with 95% confidence interval) between total treatment and comparator. Treatment-emergent adverse events defined as adverse events that started after the initial dose of study treatment or comparator and up to the EOS Abbreviations: CI, confidence interval; EOS, end of study; N, number of subjects in treatment arm; n, number of subjects with adverse event; TEAE, treatment-emergent adverse event 7.6.5. Treatment-Emergent Adverse Events TEAEs occurred in over 85% of patients in both treatment groups, with a risk difference of 1.8 (Table 28). In this table, grouped queries were created in which similar TEAEs were pooled to detect a safety signal. Individual PTs are listed under each grouped query term. The grouped queries demonstrating a frequency at least 2% higher in the cefiderocol group than in the meropenem group were UTI, arrhythmia, anemia, cardiac arrest, HTN, pleural effusion, hypomagnesemia, and hypoglycemia. For labeling, a higher cut-off of 4% rather than 2% was proposed due to a large number of TEAEs and for consistency with other recent antibacterial drug labels. Selected ARs in ≥4% of patients in the cefiderocol group were elevated liver tests, anemia, hypokalemia, diarrhea, hypomagnesemia, and atrial fibrillation. The reasons for selecting these ARs in labeling among all TEAEs occurring in at least 4% of patients are noted below.

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Reference ID: 4676324 NDA 209445 / S-002 Cefiderocol (Fetroja)

Table 28. Grouped Queries by Preferred Term, Occurring in at Least 4% of Patients in Cefiderocol Arm, Safety Population, APEKS-NP Trial Grouped Query Cefiderocol Meropenem Total Preferred Term N=148 N=150 N=298 Risk Difference Any TEAE 130 (87.8) 129 (86.0) 259 (86.9) 1.8 (-5.8, 9.5) Elevated liver tests 24 (16.2) 25 (16.7) 49 (16.4) -0.5 (-8.9, 8.0) Aspartate aminotransferase increased 10 (6.8) 6 (4.0) 16 (5.4) 2.8 (-2.3, 7.9) Alanine aminotransferase increased 9 (6.1) 6 (4.0) 15 (5.0) 2.1 (-2.9, 7.1) Gamma-glutamyltransferase 5 (3.4) 2 (1.3) 7 (2.3) 2.1 (-1.3, 5.5) increased Hepatic enzyme increased 4 (2.7) 10 (6.7) 14 (4.7) -4.0 (-8.8, 0.8) Transaminases increased 4 (2.7) 4 (2.7) 8 (2.7) 0.0 (-3.7, 3.7) Liver function test increased 2 (1.4) 0 2 (0.7) 1.4 (-0.5, 3.3) Blood alkaline phosphatase increased 1 (0.7) 1 (0.7) 2 (0.7) 0.0 (-1.9, 1.9) Liver function test abnormal 1 (0.7) 1 (0.7) 2 (0.7) 0.0 (-1.9, 1.9) Hypertransaminasemia 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Blood bilirubin increased 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Urinary tract infection (UTI) 25 (16.9) 18 (12.0) 43 (14.4) 4.9 (-3.1, 12.9) UTI 23 (15.5) 16 (10.7) 39 (13.1) 4.8 (-2.8, 12.4) Escherichia UTI 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Pyelonephritis 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Pyelonephritis chronic 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Cystitis 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) UTI bacterial 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Arrthymia 19 (12.8) 13 (8.7) 32 (10.7) 4.1 (-2.9, 11.1) Atrial fibrillation 7 (4.7) 4 (2.7) 11 (3.7) 2.0 (-2.3, 6.3) Bradycardia 3 (2.0) 2 (1.3) 5 (1.7) 0.7 (-2.2, 3.6) Tachycardia 2 (1.4) 2 (1.3) 4 (1.3) 0.1 (-2.5, 2.7) Ventricular extrasystoles 2 (1.4) 1 (0.7) 3 (1.0) 0.7 (-1.6, 3.0) Sinus tachycardia 1 (0.7) 2 (1.3) 3 (1.0) -0.6 (-2.9, 1.7) Arrhythmia 1 (0.7) 1 (0.7) 2 (0.7) 0.0 (-1.9, 1.9) Atrial flutter 1 (0.7) 1 (0.7) 2 (0.7) 0.0 (-1.9, 1.9) Cardiovascular insufficiency 1 (0.7) 1 (0.7) 2 (0.7) 0.0 (-1.9, 1.9) Extrasystoles 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Supraventricular tachycardia 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Supraventricular extrasystoles 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Anemia 18 (12.2) 13 (8.7) 31 (10.4) 3.5 (-3.4, 10.4) Anemia 12 (8.1) 12 (8.0) 24 (8.1) 0.1 (-6.1, 6.3) Iron deficiency anemia 3 (2.0) 0 3 (1.0) 2.0 (-0.3, 4.3) Anemia of chronic disease 2 (1.4) 0 2 (0.7) 1.4 (-0.5, 3.3) Hemoglobin decreased 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Iron deficiency 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Normochromic normocytic anemia 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) RBC count decreased 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Nephrogenic anemia 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Hypokalemia 16 (10.8) 23 (15.3) 39 (13.1) -4.5 (-12.1, 3.1) Hypokalemia 16 (10.8) 23 (15.3) 39 (13.1) -4.5 (-12.1, 3.1) Blood potassium decreased 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Diarrhea 13 (8.8) 13 (8.7) 26 (8.7) 0.1 (-6.3, 6.5) Diarrhea 13 (8.8) 13 (8.7) 26 (8.7) 0.1 (-6.3, 6.5)

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Grouped Query Cefiderocol Meropenem Total Preferred Term N=148 N=150 N=298 Risk Difference Pneumonia 13 (8.8) 12 (8.0) 25 (8.4) 0.8 (-5.5, 7.1) Pneumonia 11 (7.4) 8 (5.3) 19 (6.4) 2.1 (-3.4, 7.6) Lung infection 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Pneumonia bacterial 1 (0.7) 1 (0.7) 2 (0.7) 0.0 (-1.9, 1.9) Acinetobacter infection 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Pneumonia necrotising 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Pseudomonas infection 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Cardiopulmonary failure 10 (6.8) 13 (8.7) 23 (7.7) -1.9 (-8.0, 4.2) Pulmonary edema 3 (2.0) 1 (0.7) 4 (1.3) 1.3 (-1.3, 3.9) Cardiac failure 2 (1.4) 4 (2.7) 6 (2.0) -1.3 (-4.5, 1.9) Pulmonary congestion 2 (1.4) 3 (2.0) 5 (1.7) -0.6 (-3.5, 2.3) Ejection fraction decreased 2 (1.4) 0 2 (0.7) 1.4 (-0.5, 3.3) Cardiac failure congestive 1 (0.7) 1 (0.7) 2 (0.7) 0.0 (-1.9, 1.9) Right ventricular failure 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Cardiac failure acute 0 2 (1.3) 2 (0.7) -1.3 (-3.1, 0.5) Acute pulmonary edema 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Cardiopulmonary failure 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Encephalopathy 10 (6.8) 10 (6.7) 20 (6.7) 0.1 (-5.6, 5.8) Delirium 5 (3.4) 4 (2.7) 9 (3.0) 0.7 (-3.2, 4.6) Confusional state 1 (0.7) 1 (0.7) 2 (0.7) 0.0 (-1.9, 1.9) Encephalopathy 1 (0.7) 1 (0.7) 2 (0.7) 0.0 (-1.9, 1.9) Metabolic encephalopathy 1 (0.7) 1 (0.7) 2 (0.7) 0.0 (-1.9, 1.9) Abnormal behaviour 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Hypoxic-ischemic encephalopathy 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Coma 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Disorientation 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Septic encephalopathy 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Cardiac arrest 10 (6.8) 7 (4.7) 17 (5.7) 2.1 (-3.2, 7.4) Cardiac arrest 7 (4.7) 5 (3.3) 12 (4.0) 1.4 (-3.1, 5.9) Cardio-respiratory arrest 3 (2.0) 2 (1.3) 5 (1.7) 0.7 (-2.2, 3.6) Hypertension 10 (6.8) 7 (4.7) 17 (5.7) 2.1 (-3.2, 7.4) Hypertension 5 (3.4) 7 (4.7) 12 (4.0) -1.3 (-5.8, 3.2) Blood pressure increased 2 (1.4) 0 2 (0.7) 1.4 (-0.5, 3.3) Hypertensive crisis 1 (0.7) 1 (0.7) 2 (0.7) 0.0 (-1.9, 1.9) Essential hypertension 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Hypertensive heart disease 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Pleural effusion 10 (6.8) 6 (4.0) 16 (5.4) 2.8 (-2.3, 7.9) Pleural effusion 10 (6.8) 6 (4.0) 16 (5.4) 2.8 (-2.3, 7.9) Constipation 9 (6.1) 7 (4.7) 16 (5.4) 1.4 (-3.7, 6.5) Constipation 7 (4.7) 6 (4.0) 13 (4.4) 0.7 (-3.9, 5.3) Ileus paralytic 2 (1.4) 1 (0.7) 3 (1.0) 0.7 (-1.6, 3.0) Respiratory failure 8 (5.4) 6 (4.0) 14 (4.7) 1.4 (-3.4, 6.2) Acute respiratory failure 6 (4.1) 1 (0.7) 7 (2.3) 3.4 (-0.0, 6.8) Respiratory failure 2 (1.4) 3 (2.0) 5 (1.7) -0.6 (-3.5, 2.3) Hypoxia 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Respiratory acidosis 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Respiratory distress 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Hypomagnesemia 8 (5.4) 1 (0.7) 9 (3.0) 4.7 (0.8, 8.6) Hypomagnesemia 8 (5.4) 1 (0.7) 9 (3.0) 4.7 (0.8, 8.6)

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Reference ID: 4676324 NDA 209445 / S-002 Cefiderocol (Fetroja)

Grouped Query Cefiderocol Meropenem Total Preferred Term N=148 N=150 N=298 Risk Difference Candidiasis 7 (4.7) 9 (6.0) 16 (5.4) -1.3 (-6.4, 3.8) UTI fungal 4 (2.7) 2 (1.3) 6 (2.0) 1.4 (-1.8, 4.6) Oral candidiasis 2 (1.4) 0 2 (0.7) 1.4 (-0.5, 3.3) Fungal sepsis 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Candida infection 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Dermatitis diaper 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Fungal infection 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Infectious disease carrier 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Intertrigo 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Skin Candida 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Systemic Candida 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Pyrexia 7 (4.7) 6 (4.0) 13 (4.4) 0.7 (-3.9, 5.3) Pyrexia 5 (3.4) 5 (3.3) 10 (3.4) 0.1 (-4.0, 4.2) Hyperthermia 2 (1.4) 1 (0.7) 3 (1.0) 0.7 (-1.6, 3.0) Hypoalbuminemia 6 (4.1) 8 (5.3) 14 (4.7) -1.2 (-6.0, 3.6) Hypoalbuminemia 5 (3.4) 8 (5.3) 13 (4.4) -1.9 (-6.5, 2.7) Blood albumin decreased 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Tracheobronchitis 6 (4.1) 8 (5.3) 14 (4.7) -1.2 (-6.0, 3.6) Tracheobronchitis 2 (1.4) 4 (2.7) 6 (2.0) -1.3 (-4.5, 1.9) Bronchitis 2 (1.4) 3 (2.0) 5 (1.7) -0.6 (-3.5, 2.3) Bronchitis bacterial 1 (0.7) 1 (0.7) 2 (0.7) 0.0 (-1.9, 1.9) Respiratory tract infection 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Tracheitis 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Anxiety 6 (4.1) 5 (3.3) 11 (3.7) 0.8 (-3.5, 5.1) Anxiety 3 (2.0) 0 3 (1.0) 2.0 (-0.3, 4.3) Restlessness 2 (1.4) 2 (1.3) 4 (1.3) 0.1 (-2.5, 2.7) Agitation 1 (0.7) 3 (2.0) 4 (1.3) -1.3 (-3.9, 1.3) Hypoglycemia 6 (4.1) 3 (2.0) 9 (3.0) 2.1 (-1.8, 6.0) Hypoglycemia 6 (4.1) 3 (2.0) 9 (3.0) 2.1 (-1.8, 6.0) Hyperinsulinemic hypoglycemia 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Source: adae.xpt; Software: Python All values are expressed as n (%) except those in the Risk Difference column. The Risk Difference column shows absolute difference (with 95% confidence interval) between total treatment and comparator. Treatment-emergent adverse events are defined as adverse events that started after the initial dose of study treatment or comparator and up to the EOS Abbreviations: CI, confidence interval; EOS, end of study; N, number of subjects in treatment arm; n, number of subjects with adverse event; RBC, red blood cell; TEAE, treatment-emergent adverse event Infections Urinary Tract Infection While commonly reported as TEAEs in this trial, UTI and pneumonia were not generally considered as selected ARs in labeling as the study drug would not be expected to directly cause the TEAE. UTI was the most frequently reported infection-related TEAE in both treatment groups and was higher in the cefiderocol group by approximately 5%. A total of 42 patients had UTI; 24/148 (16.2%) in the cefiderocol group had a PT of UTI or E. coli UTI and 18/150 (12%) in the meropenem group had a PT of UTI, cystitis, or UTI bacterial. The Applicant provided a rationale for increased UTI, which included having a high percentage of intubated patients (60% of the study population), patients admitted in the intensive care unit (68% of the study population), and a higher chance of having a urinary catheter in these populations. The Applicant was unable to explain the increased frequency in the cefiderocol group but pointed to the successful cUTI trial data as evidence of effectiveness of cefiderocol in treatment of cUTI.

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Reference ID: 4676324 NDA 209445 / S-002 Cefiderocol (Fetroja) To gain a better understanding of the causative pathogen and treatment for these UTIs, information requests were sent to the Applicant. After several attempts at obtaining details not (b) (6) clearly available in the datasets, the following information was reported. One patient ( ) in the cefiderocol group had a known causative bacterial uropathogen (E. coli, susceptibility unknown) at day 26, which was treated with imipenem (IPM) for 3 days. The patient had P. aeruginosa NP and completed cefiderocol treatment on day 15 with clinical cure and microbiological eradication; thus, this appeared to be a new infection. Upon review of the (b) (6) narratives, an additional patient ( ) in the cefiderocol group was found to have urine culture results (C. albicans, ESBL K. pneumoniae, and P. aeruginosa) and the UTI was treated with amikacin and ceftazidime on day 19 (7 days after discontinuation of cefiderocol). While this UTI occurred after the EOT, the same pathogens present in respiratory cultures at baseline (including ESBL K. pneumoniae) were present in the urine. The remaining 40 patients did not have urine culture results. Five patients in each treatment group had a breakthrough infection (i.e., the UTI occurred before EOT). Of these five patients in each of the treatment groups, three in the cefiderocol group and four in the meropenem group were treated with nonstudy antibacterial drugs. In summary, most UTIs were new infections that occurred after the EOT. As the majority required antibacterial therapy, these were indicative of a suspected infection rather than colonization. No information about susceptibility is available to determine resistance to study drug. A sensitivity analysis excluding potentially effective concomitant antibacterial therapy (noted in Section 6.4) would be anticipated to account for antibacterial therapy given for these new infections. Pneumonia Pneumonia was reported in 13/148 (8.8%) and 12/150 (8.0%) patients in the cefiderocol and meropenem groups, respectively. With the exception of two patients in the cefiderocol group and one in the meropenem group, all of the other patients received additional antibacterial therapy for the pneumonia TEAE, indicative of suspected or confirmed infection rather than colonization. Except for one patient in the cefiderocol group, all of the pneumonia TEAEs began on or after EOT (i.e., new or recurrent infection rather than breakthrough infections). Five out of 13 patients in the cefiderocol group had at least one baseline nonfermenters (2 with A. baumannii, 2 with P. aeruginosa, and 1 with both A. baumannii and K. pneumoniae), and 2 out of 12 patients in the meropenem group had at least one baseline nonfermenter (2 with P. aeruginosa). While the frequency of pneumonia was similar in both treatment groups, five patients in the cefiderocol group and one patient in the meropenem group had both recurrence of at least one of the baseline pathogens and required additional antibacterial therapy, as noted below. In addition, (b) (6) patient ( ) in the cefiderocol group described below had baseline Acinetobacter nosocomialis and Acinetobacter spp. in cultures taken 2 days before death but did not receive antibacterial drugs. Seven patients in the meropenem group were given rescue antibacterial drugs but did not have subsequent cultures. Cefiderocol group: (b) (6) • Pneumonia bacterial – 40-year-old male with history of HTN, hemorrhagic stroke status post decompressive craniotomy, and tracheostomy developed A. baumannii VABP. Cefiderocol was discontinued on day 15 due to increased ALT and AST and thrombocytosis. On day 20, a “sanitation” bronchoscopy was performed and he had an SAE of pneumonia bacterial on day 21 for which he received ciprofloxacin and 53 Integrated Review Template, version date 2019/10/16

Reference ID: 4676324 NDA 209445 / S-002 Cefiderocol (Fetroja) tigecycline. The bronchoalveolar lavage (BAL) culture showed A. baumannii and K. pneumoniae, susceptible to cefiderocol by CLSI criteria. The clinical outcome at TOC was failure. The SAE resolved on day 37 and patient survived at EOS. (b) (6) • Lung infection – 80-year-old male with atrial fibrillation, alcoholism, and GI adenoma developed a P. aeruginosa HABP. Cefiderocol was completed on day 8 with a clinical cure. On day 20, an SAE of lung infection was treated with amikacin and piperacillin. P. aeruginosa, susceptible to cefiderocol by CLSI criteria, was noted in sputum culture. The clinical outcome at TOC was cure and relapse at FU. The SAE resolved on day 30 and the patient survived at EOS. (b) (6) • Pneumonia – 77-year-old male with COPD, myocardial ischemia, and DM developed Citrobacter freundii and Enterobacter aerogenes VABP. Cefiderocol was discontinued on day 7. On day 15, an SAE of pneumonia aspiration due to methicillin- sensitive S. aureus was reported and treated with flucloxacillin. On day 26, another SAE of pneumonia was reported and treated with ciprofloxacin, amikacin, and meropenem. A tracheal aspirate revealed susceptible E. aerogenes and E. coli. On day 32, the patient had sudden death, which was considered probably related to the new episode of pneumonia and autopsy was not performed. (b) (6) • Pneumonia – 40-year-old male with a cervical spinal cord injury secondary to a fracture developed K. pneumoniae and P. aeruginosa VABP. Cefiderocol was given until day 12. On day 19, SAEs of UTI and pneumonia occurred. The tracheal aspirate grew susceptible P. aeruginosa, which was treated with amikacin and ceftazidime. The SAE resolved on day 23 and the patient survived at EOS. The clinical outcome was cure at TOC and relapse at FU. (b) (6) • Pneumonia – 64-year-old male with HTN, COPD, pulmonary mass developed an A. baumannii, H. influenza, K. pneumoniae, and P. aeruginosa HABP for which he was given cefiderocol until day 21. On day 21, he developed a pneumonia and a tracheal aspirate showed A. baumannii for which colistin was given. There was clinical failure at TOC and survival at EOS. (b) (6) • Pneumonia – 91-year-old male with CKD, HTN, and Parkinson’s disease developed an A. nosocomialis and E. coli HABP for which cefiderocol was given until day 16. At day 14, a tracheal aspirate grew Acinetobacter spp. and E. coli at the local lab, and he was a clinical failure on that day. On day 16, he developed severe pneumonia and cardiac failure and died due to septic shock and respiratory failure. The case report form mentions that the patient died due to infection at randomization. Meropenem group: (b) (6) • Pneumonia – 79-year-old male with HTN, MI, and cardiac failure developed P. mirabilis VABP for which meropenem was given until day 10. He had a mild pneumonia on day 16, which was treated with piperacillin-tazobactam. The tracheal aspirate grew susceptible P. mirabilis, S. marcescens, and K. oxytoca. There was clinical failure at TOC and relapse at FU.

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Reference ID: 4676324 NDA 209445 / S-002 Cefiderocol (Fetroja) Candidiasis The overall frequency of candidiasis as a grouped query was slightly lower in the cefiderocol group, as noted in the table above. Candidiasis is expected to be a common AR in the study setting; the risk factors for invasive fungal disease in critically ill patients include sepsis, broad spectrum antibacterial drugs, central venous catheters, and mechanical ventilation (Muskett et al. 2011). Fungal UTI and oral candidiasis were proposed in ARs ≤4% in cefiderocol labeling. These TEAEs coincided with cefiderocol administration and required systemic antifungal treatment. However, the Applicant disagreed with adding fungal UTI as the etiology was likely due to routine urinary catheter placement in this population in an ICU setting. This was acceptable to the Division as the presence of urinary catheters in all patients with fungal UTI could not be excluded. Cardiovascular and Pulmonary Disorders Arrhythmia As a grouped query, arrhythmias occurred at a higher frequency in the cefiderocol group than in the meropenem group. The FMQ for arrhythmias shows a similar frequency of events as the reviewer-generated grouped query. Of these arrhythmias, atrial fibrillation and bradycardia were proposed as labeled ARs, over 4% and under 4%, respectively. Both ARs were previously reported in the cUTI trial as well. While most patients in the cefiderocol group with either atrial (b) (6) fibrillation or flutter had a prior history, three did not. Patien was a 71-year-old male who developed atrial fibrillation on day 7 while on cefiderocol and required heparin followed by (b) (6) acenocoumarol from day 7 to 26. Patient was a 60-year-old female with myeloma, hypothyroidism, and asthma who developed atrial fibrillation on day 1 which resolved with (b) (6) amiodarone on day 2 while still receiving cefiderocol. Patient was a 57-year-old male with DM, obstructive sleep apnea and MI who developed atrial flutter on day 4 with delirium. He was given amiodarone on day 4 and also was discontinued from the study due to “withdrawal by (b) (6) subject.” Patient , as discussed in Section 7.7.2, had unexplained bradycardia. Also, there was a greater frequency of bradycardia in the cefiderocol group in the analyses of specific vital signs, as noted in the table below. The Applicant disagreed with adding bradycardia, atrial fibrillation and flutter to labeling citing that there were no adverse findings in the TQT study and infection itself could lead to atrial fibrillation or flutter. The Division agreed with removal of bradycardia as the events were generally mild and likely confounded by concomitant medications. Hypertension The baseline frequency of HTN was over 60% in the study population. The majority of patients (b) (6) with TEAEs related to HTN had a prior history. Two patients ( ) who did not have a prior history of HTN in the cefiderocol group had a maximum postbaseline systolic blood pressure in the range of 160 to 180 mm Hg and a diastolic blood pressure in the range of 90 to 100 mm Hg. Both patients required antihypertensive medications. This TEAE was not considered an AR because alternative etiologies in a critically ill population (pain, procedures, concomitant medications) are possible. Changes in blood pressure are noted in the table below and appeared to be similar between treatment groups.

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Table 29. Subjects With Vital Sign Predefined Category Outliers at Postbaseline Safety Population Cefiderocol Meropenem Parameter (Unit) Category N=148 N=150 Systolic blood pressure (mm Hg) Value ≥160 or INC ≥20 98 (66.2) 102 (68) Value ≤90 or DEC ≥20 91 (61.5) 110 (73.3) Diastolic blood pressure (mm Hg) Value ≥105 or INC ≥15 81 (54.7) 80 (53.3) Value ≤50 or DEC ≥15 90 (60.8) 102 (68) Pulse rate (bpm) Value ≥120 or INC ≥15 84 (56.8) 84 (56) Value ≤50 or DEC ≥15 113 (76.4) 102 (68) Source: advs.xpt; Software: R All values are expressed as n (%). Abbreviations: bpm, beats per minute; DEC, decrease; INC, increase Thromboembolic Events Thromboembolic events were also proposed as ARs under 4% and are discussed in Section 7.7.2. These include arterial thromboembolic events such as MI, CVA (primary SOC, nervous system disorders), and intestinal ischemia and infarction (primary SOC, GI disorders). The FMQ for acute coronary syndrome which contains the same PTs as the myocardial ischemia and infarction also shows a greater frequency in the cefiderocol group as well. The Applicant disagreed with the inclusion of MI, intestinal ischemia, and CVA in labeling. For MI and intestinal ischemia, the Applicant stated that the TEAEs were not considered related to the drug by the investigators and that most patients had a cardiac history or other complex medical history. However, given the possible safety signal of arterial thromboembolic events and (b) (6) as certain patients did not have a significant prior history of similar events (patients and (b) (6) ), drug-induced MI or intestinal ischemia could not be excluded. It was agreed that CVA (b) (6) could be removed as patient had evidence of pre-existing artherosclerosis of the carotid arteries which may have contributed to CVA more than a drug-related etiology. Cardiac Arrest Overall, the frequency of cardiac or cardio-respiratory arrest was higher in the cefiderocol group. However, review of the individual cases showed confounding underlying medical history including DM, HTN, atherosclerosis, cardiac failure, and CKD in which relatedness to study (b) (6) drug was difficult to attribute. In the patient ( ) noted above, the MI was the likely cause of cardiac arrest. Thus, the TEAEs of cardiac arrest were considered to be a consequence of certain events and not ARs, given the underlying severity of illness in the study population. Cardiopulmonary Failure and Pleural Effusion Cardiac and pulmonary failure TEAEs that appeared to be similar in pathogenesis were (b) (6) combined, and the frequency was greater in the meropenem group. Three patients ) who did not have a prior history of cardiac failure developed pulmonary edema, but each had a history of CKD as a possible confounder. Several patients also had pleural effusion in both treatment groups. In the cefiderocol group, each of these patients had other predisposing conditions (e.g., recent surgery and bed-ridden state, cardiac failure, valvulopathy). (b) (6) One patient ( ) had SAEs of acute respiratory failure, pleural effusion, and sepsis secondary to HABP, which were considered related to cefiderocol. However, this pleural effusion was noted to be multiloculated on chest ultrasound and may have more of an empyema

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Reference ID: 4676324 NDA 209445 / S-002 Cefiderocol (Fetroja) rather than simple fluid overload given the recurrence of HABP and sepsis. Thus, these TEAEs were not proposed as ARs in labeling. Respiratory Failure The majority of patients with respiratory failure-related TEAEs had an alternative cause for respiratory failure such as fluid overload, worsening of the underlying pneumonia or a new infectious process such as aspiration pneumonia. Thus, this was not proposed as an AR in labeling. Blood and Lymphatic Disorders Anemia-related TEAEs were analyzed in detail given the siderophore-based mechanism of cefiderocol. At least 8 out of 18 patients in the cefiderocol group who developed anemia had no prior history of anemia. Although acute infection, blood draws for laboratory studies, or procedures can precipitate anemia, the frequency of anemia-related TEAEs were greater in the cefiderocol arm. There were no specific PTs suggestive of aplastic or hemolytic anemia, however, Coombs’ tests, peripheral smears, reticulocyte counts and haptoglobin were not routinely performed. The possibility of immune-related anemia secondary to cefiderocol could not be fully excluded. A few patients with anemia without prior history may have had a positive (b) (6) dechallenge with cefiderocol ( ). A few patients without a prior history (b) (6) ( ) required treatment (i.e., iron or transfusion of blood products). Maximum postbaseline decreases in hemoglobin were overall slightly worse in the cefiderocol group, as noted in the table below (Table 30).

Table 30. Maximum Postbaseline Decreases in Hemoglobin, APEKS-NP Trial Baseline Hemoglobin Gradea Cefiderocol Meropenem Postbaseline Hemoglobin Grade N=148 N=150 Total subjects (any grade) 91 (61.5) 83 (55.3) Grade 0 Grade 1 25 (16.9) 21 (14) Grade 2 8 (5.4) 11 (7.3) Grade 3 4 (2.7) 1 (0.7) Grade 1 Grade 2 31 (20.9) 20 (13.3) Grade 3 4 (2.7) 3 (2) Grade 2 Grade 3 10 (6.8) 13 (8.7) Source: ad b.xpt; Software: R All values are expressed as n (%). Laboratory grades are based on CTCAE version 5.0. Abbreviations: CTCAE, Common Terminology Criteria for Adverse Events; LLN, lower limit of normal Additional time trends for hemoglobin and hematocrit are shown in figures in Section 17. The Applicant did not agree with including anemia in the cefiderocol labeling due to the lack of a plausible mechanism and the following specific reasons were cited: the life-span of the erythrocyte is 120 days, and short-term treatment with an iron-binding chelator would not impact erythropoiesis; the nonclinical studies did not show a propensity of cefiderocol to induce red blood cell hemolysis; the clinical studies did not reveal evidence of hemolysis, although no direct tests for hemolysis were performed; including anemia would give a misleading impression that cefiderocol has a direct effect on hematologic parameters. Thus, anemia was removed from the cefiderocol labeling but will continue to be monitored for in the post-marketing setting. One

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Reference ID: 4676324 NDA 209445 / S-002 Cefiderocol (Fetroja) reassurance that the degree of anemia is not significantly worse in the cefiderocol group as compared to meropenem is that a similar number of patients required blood transfusion, as noted in Table 41. (b) (6) Thrombocytopenia and thrombocytosis were also noted as ARs. Patient had an SAE of (b) (6) thrombocytopenia as noted in Section 7.6.3. Thrombocytosis occurred in three patients ( (b) (6) ) that did not appear to have an alternative cause. Patient who had a peak platelet count of 526×109/L on day 10 seemed to have a positive dechallenge with cefiderocol. Electrolyte Abnormalities Theoretically, while siderophores have a preference for iron-binding, they can also chelate numerous other metals with variable affinities (Schalk et al. 2011). Thus, electrolyte disturbances involving cations were considered as potential ARs. Hypomagnesemia and hypokalemia occurred in ≥4% and hyperkalemia, hypocalcemia, and hyponatremia occurred in ≤4% of patients treated with cefiderocol; these were considered ARs if there was no alternative cause, if there were possible clinical consequences, or if grade 4 toxicity was present. The PT of hypomagnesemia occurred much more frequently in the cefiderocol group, with a risk difference of 4.7. Eight patients with hypomagnesemia had mild changes in magnesium with grade 0 to 1 toxicity (below lower limit of normal to 0.5 mmol/L) using the Common Terminology Criteria for Adverse Event grading system (National Cancer Institute 2017). Upon examination of hypomagnesemia in laboratory findings, more patients with hypomagnesemia (b) (6) were identified, as noted in the table below. One patient ( ) had grade 4 hypomagnesemia on day 20 (decreased from 1.86 to 0.27 mmol/L) and normalized after discontinuation of cefiderocol. Except for fluconazole, no concomitant medications were given until day 24. About 10% or more patients in both treatment groups had TEAEs of hypokalemia. Upon examination of hypokalemia in laboratory findings, more patients in the cefiderocol had toxicity grades of 3 (b) (6) or 4 , as noted in the table below. Two patients ( ) had grade 4 hypokalemia and subsequent fatal cardiac events (cardiac arrest and MI), respectively. A PT of hyperkalemia was noted in four patients in the cefiderocol group; one of these patients (b) (6) ( ) did not appear to have an alternative cause for hyperkalemia (increased potassium from 4.9 to 5.7 mmol/L) such as concomitant medications or CKD on day 4. A few patients in the cefiderocol group had grade 4 toxicity in laboratory findings for hypocalcemia and (b) (6) hyponatremia. Patient had an TEAE of hypocalcemia from day 3 to 38 with an eventual (b) (6) SAE of status epilepticus. Patient had an TEAE of hyponatremia without any apparent alternative cause.

Table 31. Laboratory Abnormalities for Electrolytes (CTCAE Version 5.0), Worsened Grade, Safety Population, APEKS-NP Trial Cefiderocol Meropenem N=148 N=150 Parameter Any Grade Grade 1-2 Grade 3-4 Any Grade Grade 1-2 Grade 3-4 Magnesium (mmol/L) - decreased 35 (23.6) 34 (23) 1 (0.7) 24 (16) 22 (14.7) 2 (1.3) Calcium (mmol/L) - decreased 49 (33.1) 34 (23) 15 (10.1) 46 (30.7) 33 (22) 13 (8.7) Potassium (mmol/L) - decreased 45 (30.4) 27 (18.2) 18 (12.2) 44 (29.3) 31 (20.7) 13 (8.7) Potassium (mmol/L) - increased 22 (14.9) 18 (12.2) 4 (2.7) 21 (14) 18 (12) 3 (2) Sodium (mmol/L) - decreased 41 (27.7) 37 (25) 4 (2.7) 55 (36.7) 47 (31.3) 8 (5.3) Source: ad b.xpt; Software: R All values are expressed as n (%).

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Laboratory grades are based on CTCAE version 5.0. Abbreviations: CTCAE, Common Terminology Criteria for Adverse Events; LLN, lower limit of normal The Applicant disagreed with inclusion of all of the electrolyte disturbances discussed above citing that there cannot be a chelating effect with cefiderocol for Mg2+ and Ca2+based on nonclinical (spectrophotometry) studies, and that there were no notable changes from baseline for potassium or calcium. However, the Division proposed to retain these ARs as there were some grade 4 changes as noted in the table above. The difference in frequency of hypomagnesemia was particularly striking, and hypokalemia has been frequently labeled in other antibacterial drug labels. The following electrolyte abnormalities were included in labeling: hypomagnesemia, hypokalemia, hyperkalemia, and hypocalcemia. Gastrointestinal Disorders GI symptoms such as nausea, vomiting, diarrhea, and abdominal pain are often considered common ARs associated with antibacterial drugs. Of these symptoms, diarrhea occurred in ≥4% of patients in both treatment groups and was considered treatment-related by the investigator in a few patients in each group. Most TEAEs of diarrhea were mild to moderate and did not lead to treatment discontinuation. A slightly higher risk difference (≤2%) was noted in the cefiderocol group than in the meropenem group for nausea, abdominal pain and constipation, as noted in the table of FMQs below. Four patients (2.7%) in each treatment group developed C. difficile (b) (6) infection or colitis. All C. difficile infections resolved except for in one patient ( ) in the cefiderocol group, in which the outcome was unknown. Hepatobiliary Disorders and Hepatic Investigations The overall frequency of any hepatic TEAE, including those in the investigations and hepatobiliary SOC, was similar in both treatment groups. Clinically significant increases in liver tests in both treatment groups are noted in Section 18 (Table 69 of treatment discontinuations, and section on Hy’s law). The Applicant did not identify any cases of Hy’s law in either treatment group. Patients in the cefiderocol group who had SAEs, treatment discontinuations, or liver events considered related to study drug are summarized below. Specific hepatic TEAE occurring in the meropenem group are not discussed below as elevated liver tests are noted as ARs in meropenem labeling. (b) (6) • had SAEs of LFT increase and hepatic enzyme increase, respectively. Both events met biochemical criteria for Hy’s law but had confounding medical history as noted in Section 17. (b) (6) • – 77-year-old male with a history of hepatomegaly had a moderate TEAE of hepatic failure and SAEs of AST (≥19x upper limit of normal [ULN]) and ALT (≥10x) increased (all with onset on day 5) for which cefiderocol was discontinued. The SAEs were assessed as related by the investigator and reviewer. (b) (6) • – 61-year-old male with no relevant medical history had an SAE of LFT increase (increased AST ≥4x ULN) and prothrombin time-INR ≥1.5x ULN on day 4, which led to discontinuation of cefiderocol. The SAE was assessed as related to multiple organ failure by the investigator and related to both multiple organ failure and cefiderocol by the reviewer. (b) (6) • – 65-year-old male with relevant medical history had an SAE of increased transaminases (AST ≥5x ULN and PT-INR ≥1.5x ULN) on day 15 which was considered

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Reference ID: 4676324 NDA 209445 / S-002 Cefiderocol (Fetroja) related per the investigator and the reviewer and resolved by day 29. The ultrasound showed diffuse hepatic parenchymal disease and acalculous cholecystitis and the gastroenterologist suspected drug-induced liver injury on top of chronic liver disease. (b) (6) • – 83-year-old male with no relevant medical history had an SAE of hepatocellular injury on day 3 along with other SAEs of lactic acidosis, intestinal infarction, and septic shock that led to death. Due to many confounders, hepatocellular injury was difficult to attribute to cefiderocol alone. (b) (6) • – 86-year-old male with no relevant medical history had a TEAE of LFT increase (AST ≥5x ULN and ALT increased ≥1.5x ULN) on day 4 for which cefiderocol was discontinued. Meropenem was started and the liver tests resolved by day 9. (b) (6) • – 64-year-old male with no relevant medical history had a TEAE of blood ALP increase ≥10x ULN on day 3 that led to treatment discontinuation. The study drugs were withdrawn as a precautionary measure with a possible relationship to linezolid. Also on day 3, the patient had a moderate TEAE of cholecystitis. Meropenem was started. The TEAE did not resolve by the time of the patient death on day 8 due to myocardial infarction. (b) (6) • – 52-year-old female with no relevant medical history had a TEAE of gamma- glutamyl transferase (GGT) increased on day 6 that was considered related to study treatment by the investigator. However, the GGT was elevated at baseline (89 U/L) and all subsequent GGT values available in the datasets were lower than at baseline. (b) (6) • – 78-year-old male with no relevant medical history had a TEAE of ALT (≥5x ULN, AST ≥4x ULN) increase on day 6 and GGT (≥5x ULN) increase on day 13, which was considered related to cefiderocol by the investigator. Cefiderocol was discontinued due to ALT increased on day 5 and AST/ALT increase resolved on day 13. (b) (6) • – 58-year-old male with no relevant medical history developed a TEAE of hypertransaminasemia on day 4 which included increased ALT (≥1.5x ULN) and GGT (≥1x ULN), which reached ≥15x ULN by day 22. No cause was identified for increased GGT after discontinuation of cefiderocol on day 15. Given the similarity to other PTs in the investigations SOC, hypertransaminasemia was included in elevated liver tests grouped query as noted in the table of TEAE ≥4% and was also added to labeling in section 6.

Table 32. Hepatic TEAEs, Safety Population, APEKS-NP Trial System Organ Class Cefiderocol Meropenem Preferred Term N=148 N=150 Any hepatic TEAE 29 (19.6) 30 (20.0) Investigations 23 (15.5) 25 (16.7) Aspartate aminotransferase increased 10 (6.8) 6 (4.0) Alanine aminotransferase increased 9 (6.1) 6 (4.0) Gamma-glutamyltransferase increased 5 (3.4) 2 (1.3) Liver function test increased 2 (1.4) 0 Transaminases increased 4 (2.7) 4 (2.7) Blood alkaline phosphatase increased 1 (0.7) 1 (0.7) Liver function test abnormal 1 (0.7) 1 (0.7) Blood bilirubin increased 0 1 (0.7) Hepatic enzyme increased 4 (2.7) 10 (6.7)

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System Organ Class Cefiderocol Meropenem Preferred Term N=148 N=150 Hepatobiliary disorders 8 (5.4) 6 (4.0) Cholestasis 2 (1.4) 0 Cholecystitis 2 (1.4) 1 (0.7) Cholelithiasis 1 (0.7) 0 Hepatic failure 1 (0.7) 0 Hepatic vein dilatation 1 (0.7) 0 Hepatomegaly 1 (0.7) 0 Hypertransaminasemia 1 (0.7) 0 Cholecystitis acute 0 1 (0.7) Hepatic cyst 0 1 (0.7) Hepatic function abnormal 0 1 (0.7) Hepatocellular injury 1 (0.7) 3 (2.0) Source: adae.xpt; Software: R All values are expressed as n (%). Abbreviations: TEAE, treatment-emergent adverse event In addition, the maximum increases liver test postbaseline are shown in the table below (Table 33).

Table 33. Maximum Increases in Liver Tests Postbaseline, Safety Population, APEKS-NP Trial (Unireview Table 59, Request 18) Maximum Cefiderocol Meropenem Test Baseline Value Increase in Value N=148 N=150 ALT (U/L) ≤ULN >ULN 39 (26.4) 46 (30.7) >3x ULN 4 (2.7) 7 (4.7) >5x ULN 1 (0.7) 5 (3.3) ULN to ≤3x ULN >3x ULN 4 (2.7) 6 (4) >5x ULN 6 (4.1) 6 (4) AST (U/L) ≤ULN >ULN 38 (25.7) 40 (26.7) >3x ULN 2 (1.4) 4 (2.7) >5x ULN 3 (2) 5 (3.3) ULN to ≤3x ULN >3x ULN 5 (3.4) 8 (5.3) >5x ULN 4 (2.7) 7 (4.7) ALP (U/L) ≤ULN >ULN 35 (23.6) 44 (29.3) >3x ULN 0 1 (0.7) ULN to ≤3x ULN >3x ULN 4 (2.7) 4 (2.7) >5x ULN 1 (0.7) 0 BILI (mcmol/L) ≤ULN >ULN 11 (7.4) 17 (11.3) >1.5x ULN 3 (2) 10 (6.7) >3x ULN 1 (0.7) 1 (0.7) >ULN >1.5x ULN 14 (9.5) 15 (10) >3x ULN 0 2 (1.3) GGT (U/L) ≤ULN >ULN 23 (15.5) 28 (18.7) >2.5x ULN 7 (4.7) 7 (4.7) >5x ULN 4 (2.7) 2 (1.3) ULN to ≤2.5x ULN >2.5x ULN 13 (8.8) 14 (9.3) >5x ULN 5 (3.4) 3 (2) >2.5x ULN to ≤5x ULN >5x ULN 4 (2.7) 5 (3.3) Source: adae.xpt and adlb.xpt; Software: R All values are expressed as n (%). Laboratory grades are based on CTCAE version 5.0. Abbreviations: ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BILI, bilirubin; CTCAE, Common Terminology Criteria for Adverse Events; GGT, gamma glutamyl transferase; ULN, upper limit of normal

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Reference ID: 4676324 NDA 209445 / S-002 Cefiderocol (Fetroja) Gall bladder disorders (cholecystitis, cholelithiasis, gallbladder pain) had been previously reported in the cUTI trial and noted as ARs in labeling. A few patients had suspected (b) (6) (b) (6) cholecystitis ( ) and cholestasis ( ) in the cefiderocol group, and these ARs were proposed in labeling (frequency under 4%). Coagulation Disorders and Iron Metabolism Based on the cUTI trial, labeling includes increased prothrombin time and prothrombin time- INR. In this trial, routine measurements aPTT and prothrombin time-INR were conducted. Of the eight patients in the cefiderocol group with baseline prothrombin time-INR values of ≤1.5 that (b) (6) increased to >1.5, only two were not on anticoagulation. Both patients ( ) had (b) (6) increased prothrombin time-INR at least 12 days after EOT with cefiderocol. Patients (b) (6) (not on anticoagulation) and (on heparin) in the cefiderocol group had an INR of 107 and 100, which was out of the normal reference range; these high values were isolated and other INR values 7 days before and after were within the normal range. It is unclear whether these INR (b) (6) values represent laboratory error. Patient was a 75-year-old male with no relevant medical history completed cefiderocol on day 9 and developed a prothrombin time-INR of 100 and an aPTT of 38 on day 22. Confounding medications included antibacterial drugs a few days prior to enrollment and miconazole until day 3. No bleeding events were reported in these eight patients. The Applicant agreed with adding prolonged prothrombin time, prothrombin time-INR, and aPTT to the ARs section in labeling.

Table 34. Maximum Postbaseline Increase in PT-INR and aPTT, Safety Population, APEKS-NP Trial Parameter Maximum Increase in Cefiderocol Meropenem Baseline Value Value N=148 N=150 PT-INR ≤1.5 >1.5 8 (5.4) 6 (4) ≥1.5 >1.5 0 (0) 2 (1.3) aPTT Any value 1-1.5 x ULN 39 (26.4) 37 (24.7) 1.5-2 x ULN 15 (10.1) 13 (8.7) 2-4 x ULN 7 (4.7) 15 (10) >=4 x ULN 2 (1.4) 2 (1.3) Source: ad b.xpt; Software: R All values are expressed as n (%). Laboratory grades are based on CTCAE version 5.0. Abbreviations: aPTT, activated partial thromboplastin time; CTCAE, Common Terminology Criteria for Adverse Events; PT-INR, prothrombin time-international normalized ratio; ULN, upper limit of normal Specialized tests for iron metabolism (hepcidin, total iron-binding capacity, iron, and transferrin saturation were performed. Changes in these parameters over time from screening to TOC did not appear to be clinically relevant. Figures demonstrating these changes are noted in Section 17. Nervous System Disorders Three patients (2.0%) and two (1.3%) in the cefiderocol and meropenem groups, respectively (b) (6) had a seizure during the study. One patient ( ) of the three in the cefiderocol group had status epilepticus, which was discussed in Section 7.6.3. The other two patients in the cefiderocol group did not have a history of seizures. One had a history of craniocerebral injury and subdural hematoma status post evacuation and developed seizures during treatment, and the other, who had a history of cerebrovascular disorder, cerebral atrophy, and hypocalcemia, developed

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Reference ID: 4676324 NDA 209445 / S-002 Cefiderocol (Fetroja) seizures 14 days after EOT. Seizure is proposed as an AR as it is associated with β-lactam therapy and was noted in both the cUTI and APEKS-NP trials. Dizziness, headache, and paresthesia are also listed as ARs under 4% in labeling as they were noted to be treatment-related by the investigator. The Applicant did not agree with adding headache as the investigator clarified that the event occurred due to malposition during prolonged infusion of study drug and there was no positive rechallenge. Hypersensitivity Reactions The grouped query for rash showed a similar frequency of rash-related TEAEs in both treatment groups (5 [3.4%] in the cefiderocol and 5 [3/3%] in the meropenem group). In the cefiderocol group, one patient each had dermatitis, dermatitis allergic, rash, rash erythematous, and skin (b) (6) irritation. One patient ( ) in the cefiderocol group had a treatment-related rash per the investigator which began on day 6 and resolved by day 11. There were three additional patients who had PTs (stridor, bronchospasm, and laryngeal edema) related to the hypersensitivity Standardised Medical Dictionary for Regulatory Activities Query. (b) (6) • – 55-year-old female with a history of asthma and COPD who received cefiderocol until day 8. On days 5 and 7, she was treated with new medications for depression (clonazepam, escitalopram, piracetam) and HTN (amlodipine). Dermatitis developed on day 20 and resolved on day 26 after treatment with chloropyramine. On day 36, she developed an SAE of inspiratory stridor which resolved with tracheoscopy and balloon dilatation. Possible etiologies of dermatitis and stridor include delayed-type hypersensitivity reaction to cefiderocol or any of the other concomitant medication or perhaps a nondrug related reaction (e.g., due to an underlying medical condition such as asthma). (b) (6) • – 82-year-old male with myasthenia gravis and interstitial lung disease who completed cefiderocol on day 22. Bronchospasm developed on day 43 and resolved by day 49 after treatment with salbutamol. The investigator did not consider the TEAE related to cefiderocol. The bronchospasm may have been related to the patient’s underlying medical conditions. (b) (6) • – 71-year-old female with asthma and CVA who completed cefiderocol on day 15. Laryngeal edema developed on day 13 and resolved by day 18 after treatment with dexamethasone. No etiology was given and the investigator did not consider the TEAE related to cefiderocol. TEAEs were also evaluated using narrow FMQs. The frequencies of certain TEAEs were similar to the reviewer created grouped queries. A risk difference of ≥2% was noted for the following FMQs: anemia, arrythmia, acute coronary syndrome, hypoglycemia, and anxiety. Hypoglycemia was not considered an AR due to confounding by underlying medical history (e.g., DM) and concomitant medications. Anxiety and insomnia was also not considered ARs due to possible alternate etiologies and narratives describing details about TEAEs in the psychiatric disoders SOC were not available.

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Table 35. FDA MedDRA Queriesa by System Organ Class Occurring at Higher Frequency in Treatment Arm Than in Comparator Arm System Organ Class Cefiderocol Meropenem Total FMQ (Narrow) N=148 N=150 N=298 Risk Difference Blood and lymphatic system

disorders Anemia 18 (12.2) 15 (10.0) 33 (11.1) 2.2 (-5.0, 9.3) Cardiac disorders Arrhythmia 18 (12.2) 12 (8.0) 30 (10.1) 4.2 (-2.7, 11.0) Acute coronary syndrome 3 (2.0) 0 3 (1.0) 2.0 (-0.2, 4.3) Myocardial infarction 3 (2.0) 0 3 (1.0) 2.0 (-0.2, 4.3) Myocardial ischemia 3 (2.0) 0 3 (1.0) 2.0 (-0.2, 4.3) Systemic hypertension 9 (6.1) 7 (4.7) 16 (5.4) 1.4 (-3.7, 6.5) Endocrine disorders Hypoglycemia 6 (4.1) 3 (2.0) 9 (3.0) 2.1 (-1.8, 5.9) Gastrointestinal disorders Nausea 4 (2.7) 2 (1.3) 6 (2.0) 1.4 (-1.8, 4.6) Abdominal pain 3 (2.0) 1 (0.7) 4 (1.3) 1.4 (-1.3, 4.0) Constipation 7 (4.7) 6 (4.0) 13 (4.4) 0.7 (-3.9, 5.4) Diarrhea 13 (8.8) 13 (8.7) 26 (8.7) 0.1 (-6.3, 6.5) General disorders and

administration site conditions Fatigue 3 (2.0) 1 (0.7) 4 (1.3) 1.4 (-1.3, 4.0) Pyrexia 7 (4.7) 6 (4.0) 13 (4.4) 0.7 (-3.9, 5.4) Hepatobiliary disorders Hepatic injury 14 (9.5) 12 (8.0) 26 (8.7) 1.5 (-4.9, 7.9) Hepatic failure 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Cholecystitis 2 (1.4) 2 (1.3) 4 (1.3) 0.0 (-2.6, 2.6) Immune system disorders Angioedema 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Infections and infestations Pneumonia 15 (10.1) 14 (9.3) 29 (9.7) 0.8 (-5.9, 7.5) Neoplasms benign, malignant and

unspecified (incl cysts and polyps) Malignancy 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Nervous system disorders Paresthesia 2 (1.4) 0 2 (0.7) 1.4 (-0.5, 3.2) Headache 3 (2.0) 1 (0.7) 4 (1.3) 1.4 (-1.3, 4.0) Seizure 3 (2.0) 2 (1.3) 5 (1.7) 0.7 (-2.2, 3.6) Dizziness 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Confusional state 6 (4.1) 6 (4.0) 12 (4.0) 0.1 (-4.4, 4.5) Psychiatric disorders Anxiety 3 (2.0) 0 3 (1.0) 2.0 (-0.2, 4.3) Insomnia 5 (3.4) 3 (2.0) 8 (2.7) 1.4 (-2.3, 5.1) Depression 3 (2.0) 2 (1.3) 5 (1.7) 0.7 (-2.2, 3.6) Psychosis 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Respiratory, thoracic and

mediastinal disorders Cough 2 (1.4) 0 2 (0.7) 1.4 (-0.5, 3.2) Bronchospasm 2 (1.4) 1 (0.7) 3 (1.0) 0.7 (-1.6, 3.0)

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System Organ Class Cefiderocol Meropenem Total FMQ (Narrow) N=148 N=150 N=298 Risk Difference Skin and subcutaneous tissue

disorders Erythema 2 (1.4) 0 2 (0.7) 1.4 (-0.5, 3.2) Source: adae.xpt; Software: Python All values are expressed as n (%) except those in the risk difference column. Risk difference column shows absolute difference (with 95% confidence interval) between total treatment and comparator. Treatment-emergent adverse events defined as adverse events that started after the initial dose of study treatment or comparator and up to the EOS The severity of an event was graded by the investigator or subinvestigator according to the following definitions: Mild: A finding or symptom is minor and does not interfere with usual daily activities; Moderate: The event causes discomfort and interferes with usual daily activity or affects clinical status; Severe: The event causes interruption of the subject’s usual daily activities or has a clinically significant effect Arrhythmia includes arrhythmia, atrial fibrillation, atrial flutter, bradycardia, extrasystoles, sinus tachycardia, supraventricular extrasystoles, supraventricular tachycardia, tachycardia, ventricular extrasystoles; Anemia includes anemia, anemia of chronic disease, hemoglobin decreased, hemorrhagic anemia, iron deficiency anemia, nephrogenic anemia, normochromic normocytic anemia; Hypoglycemia includes hyperinsulinaemic hypoglycemia, hypoglycemia; Acute coronary syndrome includes acute myocardial infarction, angina unstable, myocardial infarction; Myocardial infarction includes acute myocardial infarction, myocardial infarction; Myocardial ischemia includes acute myocardial infarction, angina unstable, myocardial infarction; Anxiety includes anxiety; Hepatic injury includes alanine aminotransferase increased, aspartate aminotransferase increased, cholestasis, hepatic failure, hepatic function abnormal, hepatocellular injury, hepatomegaly; Systemic hypertension includes blood pressure increased, essential hypertension, hypertension, hypertensive crisis; Insomnia includes insomnia; Nausea includes nausea; Paraesthesia includes hypoesthesia oral, paraesthesia; Cough includes cough, hemoptysis; Erythema includes palmar erythema, rash erythematous; Abdominal pain includes abdominal pain, abdominal pain upper, acute abdomen; Fatigue includes asthenia, fatigue, malaise; Headache includes headache; Pneumonia includes infectious pleural effusion, lung abscess, lung infection, pneumonia, pneumonia aspiration, pneumonia bacterial, pneumonia necrotising, pulmonary tuberculosis; Constipation includes constipation; Pyrexia includes hyperthermia, pyrexia; Seizure includes seizure, status epilepticus; Depression includes depressed mood, depression, persistent depressive disorder; Bronchospasm includes asthma, bronchial hyperreactivity, bronchospasm; Hepatic failure includes hepatic failure; Angioedema includes laryngeal edema; Malignancy includes lung cancer metastatic; Dizziness includes dizziness; Psychosis includes hallucination, visual; Diarrhea includes diarrhea; Confusional state includes confusional state, delirium, disorientation; Cholecystitis includes cholecystitis, cholecystitis acute, gallbladder empyema Abbreviations: CI, confidence interval; EOS, end of study; FMQ, FDA medDRA query; N, number of subjects in treatment arm; n, number of subjects with adverse event Other clinical safety assessments regarding iron metabolism, Hy’s law screening, postbaseline changes in renal function, a full listing of TEAEs by PT and SOC, TEAEs by demographic subgroups, a listing of treatment discontinuations and deaths are noted in Section 17. 7.6.6. Laboratory Findings See sections above for clinically significant laboratory findings. 7.7. Review Issues Relevant to the Evaluation of Risk 7.7.1. Important Risk Review Issue #1 Issue Analysis of ACM. Background ACM was an important review issue as the CREDIBLE-CR trial reviewed in the original NDA showed an increased frequency in mortality in patients treated with NP as well as bloodstream infections (BSIs) and sepsis. Briefly, the greatest mortality imbalance disfavoring cefiderocol was noted in the NP subgroup at day 49 [19/45 (42.2%) in the cefiderocol, 4/22 (18.2%) in best available therapy treatment groups, difference 24.0, 95% CI 2.4 to 45.7]. Also, in the cefiderocol

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Reference ID: 4676324 NDA 209445 / S-002 Cefiderocol (Fetroja) group, the majority of deaths due to treatment failure, as determined by an external adjudication committee, occurred in patients who had a baseline clinical diagnosis of NP; 13 patients had a baseline clinical diagnosis of NP among 16 patients with treatment failure. Thus, ACM was reviewed in the APEKS-NP trial to determine if there were any similarities to deaths that had occurred in the CREDIBLE-CR trial. Assessment The table below (Table 36) shows the number of deaths based on the study day on which the TEAE occurred and the corresponding SOC. The majority of deaths occurred before 14 days in the cefiderocol group and between 14 to 28 days in the meropenem group. There was no other consistent pattern among deaths based on study day. There was a slightly greater frequency of deaths related to the infections/infestations and GI disorders SOC in the cefiderocol group.

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Table 36. TEAEs Leading to Deaths by System Organ Class, Safety Population, APEKS-NP Trial Cefiderocol Meropenem N=148 N=150 14-28 14-28 Primary SOC <14 Days Days >28 Days Total <14 Days Days >28 Days Total Number of deaths 18 (12.2) 13 (8.8) 8 (5.4) 39 (26.4) 14 (9.3) 16 (10.7) 5 (3.3) 35 (23.3) Cardiac disorders 4 (2.7) 6 (4.1) 1 (0.7) 11 (7.4) 7 (4.7) 8 (5.3) 0 15 (10) Infections and infestations 3 (2.0) 3 (2.0) 3 (2.0) 9 (6.1) 2 (1.3) 2 (1.3) 2 (1.3) 6 (4.0) General disorders and administration site conditions 1 (0.7) 3 (2.0) 3 (2.0) 7 (4.7) 2 (1.3) 3 (2.0) 1 (0.7) 6 (4.0) Respiratory, thoracic and mediastinal disorders 3 (2.0) 2 (1.4) 2 (1.4) 7 (4.7) 1 (0.7) 3 (2.0) 2 (1.3) 6 (4.0) Nervous system disorders 5 (3.4) 0 0 5 (3.4) 4 (2.7) 3 (2.0) 1 (0.7) 8 (5.3) Gastrointestinal disorders 3 (2.0) 0 0 3 (2.0) 0 1 (0.7) 0 1 (0.7) Hepatobiliary disorders 1 (0.7) 0 0 1 (0.7) 0 0 0 0 Injury, poisoning and procedural complications 0 1 (0.7) 0 1 (0.7) 0 0 0 0 Investigations 1 (0.7) 0 0 1 (0.7) 1 (0.7) 0 0 1 (0.7) Metabolism and nutrition disorders 1 (0.7) 0 0 1 (0.7) 0 1 (0.7) 0 1 (0.7) Neoplasms benign, malignant and unspecified* 1 (0.7) 0 0 1 (0.7) 0 0 0 0 Vascular disorders 1 (0.7) 0 0 1 (0.7) 1 (0.7) 1 (0.7) 0 2 (1.3) Blood and lymphatic system disorders 0 0 0 0 1 (0.7) 0 0 1 (0.7) Source: adae.xpt; Software: R All values are expressed as n (%). * Neoplasms include cysts and polyps. Abbreviations: SOC, system organ class; TEAE, treatment-emergent adverse event

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Reference ID: 4676324 NDA 209445 / S-002 Cefiderocol (Fetroja) Table 37 displays the TEAEs leading to death by PT. After grouping of similar terms, the top five most commonly reported PTs leading to death were CVA, intestinal ischemia or infarction, MI, septic shock, and pulmonary embolism (PE). Cerebrovascular accident, intestinal ischemia/infarction, MI and PE were considered as special events related to thrombosis and embolism and are discussed in Section 7.7.2. Infection and respiratory-related PTs (e.g., pneumonia, septic shock, sepsis, respiratory failure, ARDS, MODS) that could indicate progression of the original NP at randomization were evaluated to analyze differences between treatment groups. The majority of patients with these PTs appeared to have worsening of the underlying NP, which may have led to subsequent death. However, the frequency of these events appeared to be relatively similar between treatment groups. Investigator and reviewer assessments of relatedness to study drug with reviewer comments for each individual patient are noted in Table 69, Section 17. The investigator assessed relatedness with a category of ‘related’ or ‘not related.’ The assessment of relatedness by the reviewer was categorized by ‘related,’ ‘not related,’ and ‘indeterminate.’ The relatedness to treatment was considered ‘indeterminate’ if there were several confounders or if the study drug had been discontinued too early to determine causality. If the death appeared to be related to the study drug, it was further categorized as a possible AR or due to lack of efficacy (LOE). Relatedness to study drug was attributed to LOE when there was evidence of clinical failure, when there was recurrence of the original pathogen(s), or when rescue antibacterial drugs were provided. The reviewer’s assessment of relatedness to study drug in the three categories discussed above showed similarities between treatment arms. In the cefiderocol group, 14 deaths were considered related to study drug (4 due to ARs, 9 due to LOE, 1 with both AR and LOE). In the meropenem group, 14 deaths were considered related to study drug (4 due to ARs, 10 due to LOE). The (b) (6) patients who experienced ARs in the cefiderocol group ( ) are (b) (6) described in Section 7.7.2 as they had serious thromboembolic events. Patient had unexpected unstable angina and MI during treatment, and this was confounded by a cardiac history. The patients who were considered to have had LOE contributing to death in both treatment groups usually had infection-related death (NP, sepsis, or septic shock due to the original baseline pathogen(s) or a complication of the underlying diagnosis (ARDS, multiorgan failure). Many of the deaths considered ‘not related’ were attributable to underlying comorbidities and to events preceding randomization. For instance, several patients in both treatment groups had CVA in the month prior to randomization, with subsequent cardiac-related deaths. The majority of poststroke deaths are attributed to neurological damage, and cardiovascular complications are the second leading cause of poststroke mortality (Chen et al. 2017).

Table 37. Deaths, Safety Population, APEKS-NP Trial Cefiderocol Meropenem Total Preferred Term N=148 N=150 N=298 Risk Difference TEAE leading to death 39 (26.4) 35 (23.3) 74 (24.8) 3.1 (-6.7, 12.9) Cerebrovascular accidenta 2 (1.4) 0 2 (0.7) 1.4 (-0.5, 3.2) Intestinal ischemiab 2 (1.4) 0 2 (0.7) 1.4 (-0.5, 3.2) Myocardial infarctionb 2 (1.4) 0 2 (0.7) 1.4 (-0.5, 3.2) Septic shock 3 (2.0) 1 (0.7) 4 (1.3) 1.3 (-1.3, 3.9) Pulmonary embolismb 3 (2.0) 2 (1.3) 5 (1.7) 0.7 (-2.2, 3.6) Acute respiratory distress syndrome 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Autonomic nervous system imbalance 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Gastrointestinal hemorrhage 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0)

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Cefiderocol Meropenem Total Preferred Term N=148 N=150 N=298 Risk Difference Blood pressure increased 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Lactic acidosis 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Lung cancer metastatic 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Peripheral vascular disorder 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Subarachnoid hemorrhage 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Sudden death 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) General physical health deterioration 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Cardiac arrestb 6 (4.1) 6 (4.0) 12 (4.0) 0.1 (-4.4, 4.5) Sepsisb 2 (1.4) 2 (1.3) 4 (1.3) 0.1 (-2.5, 2.7) Multiple organ dysfunction syndrome 4 (2.7) 4 (2.7) 8 (2.7) 0.0 (-3.6, 3.7) Pneumoniab 4 (2.7) 4 (2.7) 8 (2.7) 0.0 (-3.6, 3.7) Cardiovascular insufficiency 1 (0.7) 1 (0.7) 2 (0.7) 0.0 (-1.8, 1.9) Hepatoxicityb 1 (0.7) 1 (0.7) 2 (0.7) 0.0 (-1.8, 1.9) Intracranial pressure increased 1 (0.7) 1 (0.7) 2 (0.7) 0.0 (-1.8, 1.9) Respiratory failureb 2 (1.4) 3 (2.0) 5 (1.7) -0.6 (-3.6, 2.3) Acute abdomen 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Brain injury 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Bronchopleural fistula 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Cardiogenic shock 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Cardiovascular disorder 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Disseminated intravascular coagulation 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Encephalopathy 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Hypotension 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Hypovolemia 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Shock hemorrhagic 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Systemic inflammatory response syndrome 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Urinary tract infection 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Death (due to unknown cause) 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Brain edema 1 (0.7) 5 (3.3) 6 (2.0) -2.6 (-5.8, 0.6) Cardiopulmonary failureb 3 (2.0) 7 (4.7) 10 (3.4) -2.7 (-6.8, 1.4) Source: adae.xpt; Software: Python All values in the cefiderocol and meropenem columns are expressed as n (%). Risk difference column shows absolute difference (with 95% confidence interval) between cefiderocol and meropenem. Treatment-emergent adverse events are defined as adverse events that started after the initial dose of study treatment or comparator and up to the EOS a Cerebrovascular accident includes cerebrovascular accident, stroke in evolution; Intestinal ischemia includes intestinal infarction, intestinal ischemia; Myocardial infarction includes acute myocardial infarction, myocardial infarction, Pulmonary embolism includes pulmonary embolism, pulmonary artery thrombosis; Cardiac arrest includes cardiac arrest, cardio-respiratory arrest; Pneumonia includes pneumonia (one patient had PT of pneumonia and death for which the verbatim term was death due to pneumonia), pneumonia necrotising, pseudomonal infection; Hepatoxicity includes hepatic enzyme increased, hepatocellular injury; Respiratory failure includes acute respiratory failure, respiratory failure; Cardiopulmonary failure includes cardiac failure, cardiac failure acute, cardiac failure congestive, cardiopulmonary failure, pulmonary edema Abbreviations: CI, confidence interval; EOS, end of study; N, number of subjects in treatment arm; n, number of subjects with adverse event; TEAE, treatment-emergent adverse event Mortality by Baseline Microbiological Characteristics In patients with known MIC, whether the MIC was >8 mcg/mL for meropenem or <8 mcg/mL, the trend for ACM at the EOS was worse in the cefiderocol group as compared to the meropenem group. . Of the top five pathogens at baseline, subgroups with greater mortality in the cefiderocol group included those with A. baumannii and E. coli NP. Mortality in patients with baseline A. baumannii species was analyzed further.

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Table 38. All-Cause Mortality at EOS by Meropenem Susceptibility and Baseline Pathogens, Safety Population Cefiderocol Meropenem Risk Characteristic N=148 N=150 Difference 95% CI MIC >8 mcg/mL for meropenema No 21/89 (23.6) 19/84 (22.6) 1.0 (-11.6, 13.5) Yes 12/30 (40.0) 9/26 (34.6) 5.4 (-19.9, 30.7) Top 5 pathogens Klebsiella pneumoniae 15/48 (31.3) 14/44 (31.8) -0.6 (-19.6, 18.4) Pseudomonas aeruginosa 4/24 (16.7) 7/24 (29.2) -12.5 (-36.0, 11.0) Acinetobacter baumannii 9/23 (39.1) 7/24 (29.2) 10.0 (-17.0, 37.0) Escherichia coli 6/19 (31.6) 4/22 (18.2) 13.4 (-13.0, 39.8) Enterobacter cloacae 0/7 (0.0) 2/8 (25.0) -25.0 Source: adsl.xpt; admbo.xpt. All values in the cefiderocol and meropenem columns are expressed as n (%). Risk Difference column shows absolute difference between cefiderocol and meropenem. Confidence intervals for the risk difference, using Wald method, are computed when both arms contain at least 10 subjects in the subgroup. Subjects with unknown survival status at EOS are considered deaths. a 63 subjects have missing MIC data Abbreviations: CI, confidence interval;; EOS, end of study; MIC, minimum inhibitory concentration In patients who had A. baumannii complex (includes A. baumannii and A. nosocomialis) at baseline, there was slightly greater mortality at all the time points in the cefiderocol group than in the meropenem group., as noted in Table 39. Of these patients who died by EOS, a similar number of patients in each treatment group had meropenem nonsusceptible A. baumannii complex.

Table 39. Mortality in Patients With Baseline A. baumannii Complex Species All-Cause Mortality Cefiderocol Meropenem Difference (95% CI) Day 14 5/26 (19.2) 4/25 (16.0) 3.2 (-17.7, 24.1) Day 28a 9/26 (34.6) 6/25 (24.0) 10.6 (-14.2, 35.4) EOSa 10/26b (38.5) 7/25c (28.0) 10.5 (-15.2, 36.1) Source: adsl.xpt; admbo.xpt. All values in the cefiderocol and meropenem columns are expressed as n/N (%). 26 subjects in the cefiderocol arm and 25 subjects in the meropenem arm were known to be infected at baseline with an A. baumannii complex species. Confidence intervals for the difference in mortality rates computed using the Wald method. a One cefiderocol subject had unknown status at day 28 and at EOS and was considered as having an outcome of death. b 6 meropenem nonsusceptible, 3 meropenem susceptible,1 unknown status. c 7 meropenem nonsusceptible. Abbreviations: CI, confidence interval; EOS, end of study An additional sensitivity analysis was conducted in which clinical success was defined as clinical cure at TOC and survival at EOS. Clinical success occurred in 12/26 (46.2%) cefiderocol-treated patients and 13/25 (52.0%) meropenem-treated patients (difference: -5.8, 95% CI -33.2, 21.6). Overall outcomes in the patients with baseline A. baumannii complex appeared to be worse in patients treated with cefiderocol as compared to meropenem. However, mortality in this subset of patients in APEKS-NP trial is still within the range of mortality reported among patients with Acinetobacter infections in the ICU setting (approximately 25% in patients with susceptible strains and up to 70% in patients with carbapenem-resistant strains (Spellberg and Bonomo 2014).

Mortality by Subgroups Several subgroups were examined based on demographic variables and clinical characteristics and are shown in the next table (Table 40). The following subgroups were associated with an absolute mortality rate that was 10% higher in the cefiderocol than in the meropenem group at

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Reference ID: 4676324 NDA 209445 / S-002 Cefiderocol (Fetroja) EOS: male gender, age ≥75 years, Asian race, Asia-Pacific region, creatinine clearance <30 mL/min, and empiric treatment status of ‘yes.’ Other TEAEs were also analyzed by demographic subgroups as noted in Section 17. Compared to Asian patients in the meropenem group, Asian patients in the cefiderocol group had a higher frequency of ventilation at randomization (43.9% versus 34.9%), clinical pulmonary infection score ≥6 (14.6% versus 9.3%), disease severity (41.5% versus 23.3%), intensive care unit admission (46.3% versus 32.6%), and Acinetobacter spp. at baseline (14.7% versus 8.6%). The mean and median APACHE II score, clinical pulmonary infection score, and Sequential Organ Failure Assessment score were similar among Asian patients in both groups. There are limitations of this subgroup analysis, including the inability to adjust for multiple variables.

Table 40. Summary of All-Cause Mortality at EOS by Subgroups of Safety Population Cefiderocol Meropenem Risk Characteristic N=148 N=150 Difference 95% CI Demographic characteristics Gender Male 34/101 (33.7) 23/104 (22.1) 11.5 (-0.6, 23.7) Female 8/47 (17.0) 12/46 (26.1) -9.1 (-25.7, 7.6) Age group <65 years 18/65 (27.7) 12/58 (20.7) 7.0 (-8.1, 22.1) ≥65 to <75 years 8/43 (18.6) 14/45 (31.1) -12.5 (-30.3, 5.3) ≥75 years 16/40 (40.0) 9/47 (19.1) 20.9 (2.0, 39.7) Race* White 29/102 (28.4) 28/100 (28.0) 0.4 (-12.0, 12.8) Black or AA 0/0 (0.0) 0/1 (0.0) Asian 13/44 (29.5) 6/44 (13.6) 15.9 (-1.0, 32.8) Other 0/2 (0.0) 1/4 (25.0) -25.0 Region North America 1/6 (16.7) 0/6 (0.0) 16.7 Europe 29/99 (29.3) 29/100 (29.0) 0.3 (-12.3, 12.9) Asia-Pacific 12/43 (27.9) 6/44 (13.6) 14.3 (-2.5, 31.1) Hispanic/Latinoa Hispanic/Latino 0/4 (0.0) 0/3 (0.0) 0.0 Not Hispanic/Latino 41/140 (29.3) 34/139 (24.5) 4.8 (-5.6, 15.2) Clinical characteristics Diagnosis at baseline HABP 19/60 (31.7) 15/61 (24.6) 7.1 (-8.9, 23.1) VABP 18/60 (30.0) 18/65 (27.7) 2.3 (-13.6, 18.2) HCABP 5/28 (17.9) 2/24 (8.3) 9.5 (-8.5, 27.5) APACHE II score ≤15 17/75 (22.7) 13/78 (16.7) 6.0 (-6.6, 18.6) 16-19 10/32 (31.3) 7/26 (26.9) 4.3 (-19.1, 27.8) ≥20 15/41 (36.6) 15/46 (32.6) 4.0 (-16.0, 24.0) CPIS <6 17/74 (23.0) 19/91 (20.9) 2.1 (-10.6, 14.8) 6-7 20/60 (33.3) 8/40 (20.0) 13.3 (-3.9, 30.5) 8-9 5/12 (41.7) 6/16 (37.5) 4.2 (-32.5, 40.8) >9 0/2 (0.0) 2/3 (66.7) -66.7 Bacteremia status No 37/135 (27.4) 30/134 (22.4) 5.0 (-5.3, 15.3) Yes 5/13 (38.5) 5/16 (31.2) 7.2 (-27.6, 42.1)

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Cefiderocol Meropenem Risk Characteristic N=148 N=150 Difference 95% CI Creatinine clearance >120 mL/min 4/22 (18.2) 4/26 (15.4) 2.8 (-18.5, 24.1) >80-120 mL/min 11/33 (33.3) 7/35 (20.0) 13.3 (-7.5, 34.2) >50-80 mL/min 11/44 (25.0) 6/37 (16.2) 8.8 (-8.7, 26.2) 30-50 mL/min 7/29 (24.1) 13/32 (40.6) -16.5 (-39.6, 6.6) <30 mL/min 9/20 (45.0) 5/20 (25.0) 20.0 (-8.9, 48.9) MDRD-eGFR ≥90 9/35 (25.7) 10/47 (21.3) 4.4 (-14.2, 23.1) 60 to <90 14/50 (28.0) 8/39 (20.5) 7.5 (-10.3, 25.2) 30 to <60 12/43 (27.9) 10/43 (23.3) 4.7 (-13.8, 23.1) 15 to <30 4/9 (44.4) 4/10 (40.0) 4.4 <15 3/11 (27.3) 3/11 (27.3) 0 (-37.2, 37.2) Empiric treatment failure status No 26/99 (26.3) 25/102 (24.5) 1.8 (-10.3, 13.8) Yes 16/49 (32.7) 10/48 (20.8) 11.8 (-5.6, 29.3) ICU admission No 6/45 (13.3) 5/51 (9.8) 3.5 (-9.3, 16.4) Yes 36/103 (35.0) 30/99 (30.3) 4.6 (-8.3, 17.6) Ventilation status No 10/57 (17.5) 9/63 (14.3) 3.3 (-9.9, 16.4) Yes 32/91 (35.2) 26/87 (29.9) 5.3 (-8.5, 19.0) Source: adsl.xpt. All values in the cefiderocol and meropenem columns are expressed as n/N’ (%) unless specified otherwise. Confidence intervals for the risk difference, using Wald method, are computed when both arms contain at least 10 subjects in the subgroup. Note: Subjects with unknown EOS survival status are considered deaths * 1 subject has unknown race a 12 subjects have unknown status Abbreviations: AA, African American; APACHE, Acute Physiology and Chronic Health Evaluation; CI, confidence interval; CPIS, clinical pulmonary infection score; eGFR, estimated glomerular filtration rate; EOS, end of study; HABP, hospital-acquired bacterial pneumonia; HCABP, healthcare-associated bacterial pneumonia; ICU, intensive care unit; MDRD, Modification of Diet in Renal Disease; MIC, minimum inhibitory concentration; VABP, ventilator-associated bacterial pneumonia Mortality by Blood Transfusion As cefiderocol acts as a siderophore and there was theoretical concern of decreased uptake in bacterial cells in a state of iron excess, mortality was analyzed based on receipt of blood transfusion. There is no increased receipt of blood transfusions nor an increased risk of mortality in patients receiving blood transfusion in either treatment group.

Table 41. All-Cause Mortality by Receipt of Blood Transfusion Cefiderocol Meropenem N=148 N=150 Risk Receipt of Transfusion n/N’ (%) n/N’ (%) Difference Blood transfusion 10/33 (30.3) 14/31 (45.2) -14.9 No blood transfusion 29/115 (25.2) 21/119 (17.6) 7.6 Source: adsl.xpt and admh.xpt; Software: R All values in the cefiderocol and meropenem columns are expressed as n/N’ (%). Conclusions An analysis of mortality by the different parameters discussed above showed that overall mortality in patients was relatively similar in both treatment groups. There was a greater frequency of deaths due to thromboembolic events in the cefiderocol group, and this will be discussed further below. In patients with Acinetobacter spp. at baseline, there was also a slightly

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Reference ID: 4676324 NDA 209445 / S-002 Cefiderocol (Fetroja) higher increased mortality in the cefiderocol group; however, the actual number of deaths was similar, and the groups were relatively small. 7.7.2. Important Risk Review Issue #2 Issue Increased frequency of serious thromboembolic events in the cefiderocol group Background A review of the fatal outcomes suggested a possible pattern of thromboembolic events. We therefore examined the safety population using a custom query and stratified the output on the basis of arterial and venous events. Since venous events may occur as a result of immobility due to hospitalization, arterial events were examined separately. Assessment Eleven (7.4%) patients in the cefiderocol group and three (2.0%) patients in the meropenem group had a thromboembolic TEAE considered related to arterial circulation. Of these 11, all but 2 were SAEs (1 developed nonserious unstable angina, but progressed to acute MI; 1 was a nonserious CVA). Of the 11, 9 had fatal outcomes by EOS. MI (including acute MI) and CVA (including cerebral ischemia and stroke in evolution) occurred in ≥2% of patients in the cefiderocol group whereas no patient had MI and 1.4% had CVA (including lacunar stroke) in the meropenem group.

Table 42. Thrombotic and Embolic TEAEs, APEKS-NP Trial Cefiderocol (N=148) Meropenem (N=150) RD Per Preferred Term Events n (%) Events n (%) Hundred Arterial thrombosis 12 11 (7.4) 3 3 (2.0) 5.4 Acute myocardial infarction 2 2 (1.4) 0 1.4 Angina unstable 1 1 (0.7) 0 0.7 Cerebral ischemia 1 1 (0.7) 0 0.7 Cerebrovascular accident 3 3 (2.0) 1 1 (0.7) 1.3 Femoral artery embolism 0 1 1 (0.7) -0.7 Intestinal infarction 1 1 (0.7) 0 0.7 Intestinal ischemia 1 1 (0.7) 0 0.7 Intracardiac thrombus 1 1 (0.7) 0 0.7 Lacunar stroke 0 1 1 (0.7) -0.7 Myocardial infarction 1 1 (0.7) 0 0.7 Stroke in evolution 1 1 (0.7) 0 0.7 Venous thrombosis 8 5 (3.4) 6 6 (4.0) -0.6 Deep vein thrombosis 1 1 (0.7) 0.7 Post thrombotic syndrome 1 1 (0.7) 0.7 Pulmonary artery thrombosis 3 3 (2.0) 3 3 (2.0) 0.0 Pulmonary embolism 1 1 (0.7) 2 2 (1.3) -0.7 Venous thrombosis 2 1 (0.7) 1 1 (0.7) 0.0 Source: Reviewer Table, created in MAED. Abbreviations: RD, risk difference; TEAE, treatment-emergent adverse event While the majority of patients in both treatment groups had underlying comorbidities that would predispose them to thromboembolic events, some of the patients had either less confounding medical histories or the event of interest was more unexpected. These cases are noted below. Of note, none of the events were related to study drug per the investigator.

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(b) (6) • – 59-year-old male with DM and HTN was diagnosed with a P. aeruginosa VABP and randomized to cefiderocol. He had had a prolonged hospitalization and pleural drainage on day 1 for hydropneumothorax. On day 5, he developed bradycardia (pulse 43 beats/minute), and SAEs of acute MI and cardiac arrest which resolved with medical management. The AST and ALT increased to ≥10x ULN and were attributed to cardiac arrest. Cefiderocol treatment was completed on day 8. The aPTT increased to 52 seconds. On day 9, he developed multiple organ dysfunction and died. Autopsy showed postinfarction cardiosclerosis, pneumonia, liver cirrhosis, and acute respiratory insufficiency. (b) (6) • – 69-year-old female with obesity, CHF, and COPD developed a closed craniocerebral injury on day -16 and was randomized to cefiderocol for an A. baumannii HCABP on day 1. Six days after completion of cefiderocol treatment, she had an SAE of CVA which resolved with sequelae (regression of cognitive and motor impairment). Trauma as a cause of craniocerebral injury was not reported. Of note, the Applicant reported that the duplex scan at the time of craniocerebral injury had shown atherosclerotic disease of the carotid arteries. Given this pre-existing condition, CVA was considered to be less likely due to study treatment. (b) (6) • – 73-year-old female with pulmonary tuberculosis 2 years prior and a neck mass s/p excision with lung metastasis was randomized to cefiderocol for A. baumannii VABP. On day -3, she received a blood transfusion for anemia and developed postprocedural hemorrhage on day 3. On days 4 and 5, the patient had severe hypokalemia (potassium decreased from 3.5 to 1.8 mg/dL) and mild chest pain which resolved the next day with potassium and tramadol, respectively. On day 14, an electrocardiogram showed anterior wall ischemia and ST depression, and an SAE of acute MI was reported on day 15. The hemoglobin decreased from 91 to 75 g/L and platelets decreased from 269 to 32×109/L. The aPTT increased to 48 from 25 at baseline. Cefiderocol was withdrawn the same day. On day 16, the patient had a cardiorespiratory arrest and the family withdrew care. She died on day 16 due to acute MI. (b) (6) • – 84-year-old female with emphysema, intracranial aneurysm, and subarachnoid hemorrhage diagnosed 20 years ago was randomized to cefiderocol for E.coli VABP. On day 10, she had an SAE of intestinal ischemia. Cyanosis and coldness of the lower limbs were noted and CT confirmed intestinal ischemia, poor contrast enhancement of the small intestine, marked gas in the intestine, portal vein gas, and suspicion of GI necrosis. Due to the patient’s age, she was monitored conservatively. On the same day, she developed hypotension and bradycardia and died due to intestinal ischemia. The last day of study drug was day 8. The frequency of TEAEs related to venous circulation was similar in both groups. Four patients in each treatment group (2.7% in the cefiderocol and 2.6% in the meropenem group) had PE or pulmonary artery thrombosis (an essentially synonymous term). Risk factors for PE include prolonged immobilization, recent surgery, cancer, and recent CVA. The risk of deep vein thrombosis is elevated in the first 1 to 3 months after CVA, in part due to stroke-related immobility, and PE is the most common cause of death at its peak occurrence about 2 to 4 weeks after stroke onset (Kelly et al. 2001). Of these four patients in the cefiderocol group, three had had a CVA within the past month, and one had recent HTN-induced intracerebral hemorrhage.

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Reference ID: 4676324 NDA 209445 / S-002 Cefiderocol (Fetroja) Despite anticoagulation, all four had fatal outcomes that appeared to be related to the PE. In summary, venous thromboembolic events were more likely to be due to these alternate etiologies. Conclusion Due to the increased frequency and timing of these TEAEs in relationship to study drug administration, a drug-induced effect cannot be fully excluded. Given the potential safety risk of thromboembolic events in this trial, cefiderocol labeling will include individual PTs (MI and intestinal ischemia) at a frequency of ≤4% each. The Applicant justified the rationale for exclusion of CVA in labeling which was agreeable to the Divison (see Section 7.6.5). Routine postmarketing surveillance will be recommended to monitor for such events. The approved labeling of meropenem (section 6, systemic ARs) mentions pulmonary embolus and MI. 7.7.3. Important Risk Review Issue #3 Issue MIC increases during treatment. Background Resistance development during treatment could result in treatment failure. The relationship of a ≥ four-fold increase in MIC from baseline to treatment outcome was examined in the two treatment arms. Assessment A total of 19 subjects (9 in the cefiderocol arm and 10 in the meropenem arm) had isolates which showed a four-fold increase in MIC to the study drug (Table 43). In the cefiderocol arm, all except one subject had persistence of the baseline pathogen at TOC or had died. Three of the nine subjects with baseline A. baumannii or K. pneumoniae died and five subjects were clinical failures. One subject with K. pneumoniae developed resistance to cefiderocol (MIC >8 mcg/mL). Two subjects with A. baumannii had MIC increases and one subject died. In the meropenem arm, four had clinical failure at TOC and one died. Four-fold increases in MIC with subsequent death were evaluated to determine clinical correlation; there were four and one patient in the cefiderocol and meropenem groups, respectively. Table 70 provides details for each patient. Of the four patients in the cefiderocol (b) (6) group, two involved treatment failure/lack of efficacy (patient ). In both cases, there was a recurrence of pneumonia with at least one baseline pathogen (Enterobacterales) and (b) (6) treatment with rescue antibacterial drugs. Another patient ( ), had a sudden death with unknown cause and autopsy results were unavailable. The death was assessed as indeterminate (b) (6) due to very limited information leading up to the sudden death. Lastly, one patient ( ) had autopsy results showing no pneumonia but a hemorrhagic CVA and brain edema as a cause of (b) (6) death; this death was assessed as not related. In the meropenem group, patient had a recurrence of the baseline pathogen and was assessed as having had lack of efficacy, but treatment with rescue antibacterial drugs was not given.

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Reference ID: 4676324 NDA 209445 / S-002 Cefiderocol (Fetroja) Conclusion A four-fold MIC increase was noted in a similar number of patients in both treatment groups. However, more patients in the cefiderocol group had an unfavorable outcome (i.e., clinical failure or death, 8/9 in the cefiderocol and 5/10 in the meropenem group). Among patients who had a four-fold MIC increase and death, two patients in the cefiderocol group and one in the meropenem group had death involving lack of efficacy for treatment of the baseline NP.

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Table 43. Subjects With 4-Fold-Increase in Cefiderocol MIC During Treatment Microbiological Clinical Treatment Pathogen With 4- MIC Increase(Specimen; Outcome at Outcome at USUBID Arm Baseline Pathogen Fold MIC Increase Day) TOC TOC (b) (6) Cefiderocol Acinetobacter Acinetobacter 0.25 to 1 (BAL; day 3) Indeterminate Indeterminate baumannii baumannii Cefiderocol Enterobacter Enterobacter 0.12 to 0.5 (sputum; day 3) Indeterminate Failure aerogenes aerogenes Cefiderocol Citrobacter freundii; Enterobacter 0.06 to 0.5 (sputum; day 3) Persistence Failure Enterobacter aerogenes 0.06 to 0.25 (Tracheal aerogenes aspirate; day 15) Cefiderocol Klebsiella pneumoniae Klebsiella 0.25 to 1 Persistence Indeterminate pneumoniae (Tracheal aspirate, day 17) Cefiderocol Klebsiella pneumoniae Klebsiella ≤0.03 to >8 Persistence Cure pneumoniae (Tracheal aspirate; day 15) Cefiderocol Enterobacter cloacae; Enterobacter 1 to 4 Persistence Failure Serratia marcescens cloacae (Tracheal aspirate; day 11) Serratia 0.06 to 0.25 marcescens (sputum; day 4) Cefiderocol Acinetobacter Acinetobacter 0.12 to 2 Persistence Failure baumannii baumannii (Tracheal aspirate; day 3, day 22 and day 31) Cefiderocol Klebsiella pneumoniae Klebsiella ≤0.03 to 0.12 Persistence Indeterminate pneumoniae (Tracheal aspirate; day 15) Cefiderocol Klebsiella pneumoniae Klebsiella 0.06 to 0.25 (BAL; day 3) Indeterminate Failure pneumoniae Meropenem Acinetobacter Klebsiella 2 to 8 (BAL; day 4) Eradication Failure baumannii; Klebsiella pneumoniae pneumoniae Meropenem Pseudomonas Pseudomonas 0.12 to 64 (BAL; day 4) Eradication Failure aeruginosa aeruginosa Meropenem Acinetobacter Acinetobacter 1 to 64 (Tracheal aspirate; Indeterminate Failure baumannii baumannii day 3) Meropenem Acinetobacter Acinetobacter 1 to 32 (BAL; day 10) Persistence Cure baumannii baumannii 1 to >64 (Tracheal aspirate; day 3) Meropenem Pseudomonas Pseudomonas 0.25 to 4 (Tracheal Indeterminate Cure aeruginosa aeruginosa aspirate; day 15 and day 22)

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Microbiological Clinical Treatment Pathogen With 4- MIC Increase(Specimen; Outcome at Outcome at

USUBID (b) (6) Arm Baseline Pathogen Fold MIC Increase Day) TOC TOC Meropenem Klebsiella pneumoniae; Pseudomonas 0.12 to 16 (Tracheal Indeterminate Indeterminate Pseudomonas aeruginosa aspirate; day 11) aeruginosa Meropenem Klebsiella pneumoniae; Pseudomonas 0.25 to 4 (Tracheal Persistence Cure Pseudomonas aeruginosa aspirate; day 15) aeruginosa Meropenem Citrobacter freundii; Citrobacter freundii ≤0.03 to 0.12 Eradication Cure Enterobacter asburiae (Tracheal aspirate; day 3) Meropenem Acinetobacter Acinetobacter 0.12 to >64 Persistence Failure baumannii baumannii (Tracheal aspirate; day 14 and day 21) Meropenem Acinetobacter Acinetobacter 0.12 to >64 Persistence Cure baumannii; baumannii (Sputum; day 8) Pseudomonas aeruginosa; Stenotrophomonas maltophilia Source: Reviewer analysis using MICROB.xpt Subjects shown in red died; Bacteria in blue considered as colonizers; Abbreviations: BAL, bronchoalveolar lavage; MIC, minimum inhibitory concentration; TOC, test-of-cure

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7.7.4. Important Risk Review Issue #4 No further issues identified. 8. Therapeutic Individualization 8.1. Intrinsic Factors Renal function was identified to be the only intrinsic factor warranting dose adjustment. The clinical pharmacology review from the original NDA presented dose adjustments for patients with creatinine clearance (CLcr) <60 mL/min including end-stage renal disease (ESRD) patients with intermittent hemodialysis and for patients with CLcr ≥120 mL/min. In addition, we also recommended dose adjustment for patients receiving CRRT. However, it was determined not to include the dosage adjustment for patients receiving CRRT in the labeling at that time because it was agreed that CRRT would not be required in patients with the cUTI, the indication that Fetroja was being labeled for. In this submission, the Applicant included additional in vitro and clinical data that support the recommendation of dose adjustment for patients receiving CRRT. The current review focuses on dose adjustments in patients receiving CRRT based on additional data submitted in this sNDA. Patients Receiving Continuous Renal Replacement Therapy Critically ill patients with AKI may be required to receive CRRT including continuous venovenous hemofiltration (CVVH), continuous venovenous hemodialysis (CVVHD), or continuous venovenous hemodiafiltration (CVVHDF). Cefiderocol is supposed to be cleared by CRRT. Therefore, specific dose adjustment needs to be considered for patients receiving CRRT. CRRT Dose Adjustment in Phase 2 and Phase 3 Studies The Applicant adjusted cefiderocol dose at 1 g q12h, 1.5 g q12h, and 1.5 g q12h for patients receiving CVVH, CVVHD, and CVVHDF, respectively, in the CREDIBLE-CR and APEKS-NP trials. The rationale for this dose adjustment is described below. For patients receiving CRRT, drug clearance (CL) is calculated by the equation CL = CLnonrenal+CLCRRT, where CLnonrenal is the remaining systemic clearance of cefiderocol in this patient population that is largely attributed from nonrenal CL, and CLCRRT is the clearance by ultrafiltration or dialysis of CRRT. When proposing the above mentioned CRRT-mode based dose adjustments, the Applicant estimated the CLCRRT for cefiderocol by using the reported CLCRRT of cefepime by CVVH or (b) (4) CVVHD/CVVHDF since the molecular weights of both drugs are in the similar scale

was corrected when estimating the CLCRRT of cefepime by CVVH or CVVHD/CVVDF for cefiderocol. In the CREDIBLE-CR and APEKS- NP studies, observed cefiderocol concentration-time profiles were available from a total of 12 patients receiving CRRT who were treated with cefiderocol at the above-mentioned dose adjustments. As shown in Figure 2, the plasma cefiderocol concentrations from these patients were within the range of plasma concentrations for the patients without hemodialysis, CVVH, or CVVHDF.

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Figure 2. Observed Plasma Cefiderocol Concentration Profiles for Patients With or Without Hemodialysis in CREDIBLE-CR and APEKS-NP Studies

Source: Figure 2.7.7-16 from 2.7.2 Summary of Clinical Pharmacology – HABP/VABP Abbreviations: CVVH, continuous venovenous hemofiltration; CVVHD, continuous venovenous hemodialysis; CVVHDF, continuous venovenous hemodiafiltration; HD, hemodialysis

Recommended Effluent Flow Rate (QE)-Based Dose Adjustments in Patients Receiving CRRT The FDA’s clinical pharmacology review team considers that it is not appropriate to recommend one fixed dose regimen for all patients requiring CRRT, either by CVVH or CVVHD/CVVHDF, as administered in CREDIBLE-CR and APEKS-NP studies because QE, that is presumed to determine CLCRRT may vary among patients receiving CRRT. The review team conducted separate analyses and recommended a QE-based dose adjustment, as described below. As stated above, CL of cefiderocol in patients receiving CRRT is calculated by the equation CL = CLnonrenal+CLCRRT. CLnonrenal of cefiderocol was estimated to be 1.14 L/h, which is the value in subjects with ESRD (study 1222R2113: PK study in subjects with renal impairments). CLCRRT is estimated by the equation CLCRRT = QE×SC or SA (Pistolesi et al. 2019). QE is determined by the CRRT conditions, such as ultrafiltration rate for CVVH, dialysis rate, and ultrafiltration rates for CVVHD and CVVHDF, pre- or postfilter replacement fluid flow rate, as well as other factors, such as patient’s body weight. SC represents sieving coefficient for convective CRRT modality (e.g., CVVH) and SA represents saturation coefficient for diffusive CRRT modality (e.g., CVVHD). For drugs with molecular weight <1000 Da, it can be assumed that entire free drug can cross the membrane and SC can be approximated to free (i.e., unbound) fraction of drug in plasma (fu) (Pistolesi et al. 2019). Likewise, the SA value for drugs with molecular weight <500 Da is generally superimposable to fu (Pistolesi et al. 2019). Hence, CLCRRT of cefiderocol can be calculated as CLCRRT = QE×fu, with fu =0.422 for cefiderocol, regardless of CRRT modality. Therefore, cefiderocol CL in patients receiving CRRT depends on patient’s CLnonrenal

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and QE (i.e., CL = CLnonrenal+QE×fu). Because QE varies with prescriptions of CRRT in different clinical settings and different patient conditions, cefiderocol dosage in patients receiving CRRT is required to be adjusted as a function of QE under the assumption that CLnonrenal is not substantially changed in patients receiving CRRT. Therefore, the CRRT-mode based dose adjustments in phase 2 and phase 3 studies are not appropriate to accommodate the various clinical settings where QE varies substantially. Thus, we recommend a QE-based dose adjustment because QE is a net input for determining cefiderocol clearance by CRRT. In addition, the Applicant conducted an in vitro CRRT study in order to identify CRRT features that could impact the clearance of cefiderocol by CRRT (refer to Section 14.1 ). These CRRT (b) (4) features include CRRT mode (CVVH versus CVVHD), filter type (b) (4) , point of dilution , and QE (2 versus 4 L/h). The results showed that CRRT mode, filter type, and point of dilution did not have significant effect on the clearance by CRRT. However, QE made a significant difference in the calculation of CLCRRT. This confirms our recommendation of QE-based dose adjustment. Cefiderocol dosing regimens in patients undergoing CRRT were then determined based on drug clearance estimated by CL = CLnonrenal+QE×fu. With a clinically relevant QE range (0.5 to 5 L/h), an average CLnonrenal value from patients with ESRD (i.e., 1.14 L/hr), and an unbound fraction in plasma of 0.422, cefiderocol daily doses were calculated for patients receiving CRRT (Table 44). These doses are expected to provide exposure comparable to the average daily area under the concentration-time curve (AUC, 1,560 mcg∙hr/mL) obtained in patients with HABP/VABP from CREDIBLE-CR and APEKS-NP studies. Note that, in this analysis, we presumed that CLnonrenal is not substantially changed in patients receiving CRRT. In addition, we confirmed that the effect (b) (4) of % prefilter replacement fluid on cefiderocol CL is not clinically relevant in patients receiving CRRT (the data are not included).

Table 44. Determination of Cefiderocol Daily Doses for Patients Receiving CRRT According to Effluent Flow Rate (QE) QE (L/hr) 0.5 1 2 3 4 5 a CLCRRT (L/hr) 0.211 0.422 0.844 1.27 1.69 2.11 CL (L/hr)b 1.35 1.56 1.98 2.41 2.83 3.25 Darily dose (grams)c 2.11 2.44 3.10 3.75 4.41 5.07 Source: Clinical Pharmacology Review Team’s assessments a CLCRRT = QE×fu (fu of cefiderocol =0.422) b CL = CLCRRT+CLnonrenal (CLnonrenal of cefiderocol =1.14 L/hr) c Daily Dose = target daily AUC×CL (target daily AUC =1,560 mcg∙hr/mL) Abbreviations: CL, clearance; CRRT, Continuous Renal Replacement Therapy

Based on the results of above analyses, the QE- based cefiderocol dose regimens for patients receiving CRRT were recommended as shown in Table 45.

Table 45. Recommended Dose Regimens Adjusted Based on Effluent Flow Rates (QE) for Patients Receiving CRRT QE Dose Regimens 2 L/hr or less 1.5 grams q12h 2.1 to 3 L/hr 2 grams q12h 3.1 to 4 L/hr 1.5 grams q8h 4.1 L/hr or greater 2 grams q8h Source: Adapted from Table S1 in the Applicant’s study report of s-649266-cpk-007-c Abbreviations: CRRT, continuous renal replacement therapy; q8h, every 8 hours; q12h, every 12 hours

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Prediction of Cefiderocol PK Profiles in Phase 3 CRRT Patients at the Recommended QE- Based Dosing Regimens

Of the 12 CRRT patients from phase 3 studies who provided observed PK data, records of QE were available from 9 patients. The Applicant predicted PK profiles of cefiderocol in nine patients at the dose regimens adjusted by their actual QE according to Table 45, using the post hoc PK parameters that were estimated from a population PK model developed with pooled PK data from phase 1, phase 2, and 3 studies (refer to Section 14.3). Predicted plasma concentrations in the nine patients receiving CRRT are presented in Figure 3 and are superposed with the prediction interval of plasma concentrations in patients not receiving CRRT who were dosed at 2 g every 8 hours. As shown in Figure 3, plasma concentrations of cefiderocol predicted at the recommended QE–based dose regimens (Table 45) in patients receiving CRRT were similar to those at 2 g q8h in patients not receiving CRRT. The predicted geometric means of Cmax and daily AUC in patients receiving CRRT were 107 mcg/mL and 1553 mcg·hr/mL, respectively, which are similar to those from patients with HABP/VABP in phase 3 studies (geometric means Cmax of 99.7 mcg/mL, daily AUC of 1560 mcg·hr/mL), demonstrating that the recommended QE–based dose regimens (Table 45) would provide adequate exposure of cefiderocol in patients receiving CRRT.

Figure 3. Predicted Plasma Concentrations in Patients Receiving CRRT at the Recommended QE- Based Dose Regimens and Prediction Interval of Plasma Concentrations for Patients Not Receiving CRRT at 2 g q8h

Source: Figure 1 from the Applicant’s study report of s-649266-cpk-007-c Abbreviations: CRRT, continuous renal replacement therapy; q8h, every 8 hours; q12h, every 12 hours 8.2. Drug Interactions No updates on drug-drug interactions from the review of original NDA. 8.3. Pediatric Labeling/Plans for Pediatric Drug Development The initial pediatric study plan (iPSP) was agreed to March 4, 2017, and the amended iPSP for the original NDA was issued by the Division on November 26, 2018. Two pediatric 82 Integrated Review Template, version date 2019/10/16

Reference ID: 4676324 NDA 209445 / S-002 Cefiderocol (Fetroja) Postmarketing Requirements (PMRs) were agreed to by the Applicant at the time of approval of the original NDA: PMR 3744-1: Conduct an open-label randomized multicenter, active-controlled trial to evaluate the PK, safety, and tolerability of Fetroja (cefiderocol) in children from 3 months to less than 18 years of age with cUTI. The dose for this study for children 3 months to less than 18 years of age will be determined by the data from a single-dose, noncomparative study assessing the PK of Fetroja (cefiderocol) in pediatric patients from 3 months to less than 12 years of age with suspected or confirmed gram-negative infections. Draft Protocol Submission: Submitted [December 5, 2018] Final Protocol Submission: Submitted [July 26, 2019] Study Completion: 12/2023 Final Report Submission: 04/2024 [from iPSP]

PMR 3744-2: Conduct an open-label, single arm noncomparative study to evaluate the PK, safety, and tolerability of multiple doses of Fetroja (cefiderocol) in children from birth to less than 3 months of age with suspected or confirmed cUTI. The dose for this study will be determined by the data from a single-dose, noncomparative study assessing the PK of Fetroja (cefiderocol) in pediatric patients from birth to less than 3 months of age with suspected or confirmed gram-negative infections. Draft Protocol Submission: Submitted [Aug 29, 2019] Final Protocol Submission: 06/2022 Study Completion: 08/2024 Final Report Submission: 01/2025 [from iPSP] The following information was conveyed to the Applicant: (b) (4)

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8.4. Pregnancy and Lactation See the original review of NDA 209445 (Division of Anti-Infectives 2019). The Applicant did not submit additional nonclinical reproductive toxicology data in this amendment and none were necessary to support the proposed additional clinical indications. Minor changes (regarding exposure multiples) to section 8.1 in labeling were based on human PK data from a clinical study to support the new indication and not on new nonclinical or animal data. 9. Product Quality The Applicant proposes to use the currently approved and marketed drug product, Fetroja for injection, for the proposed new indication. The drug product formulation remains the same as currently approved in the NDA. Hence, there is no new product quality (chemistry, manufacturing, and controls [CMC]) information associated with this sNDA. 9.1. Device or Combination Product Considerations This section is not applicable to the sNDA.

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Reference ID: 4676324 NDA 209445 / S-002 Cefiderocol (Fetroja) 10. Human Subjects Protections/Clinical Site and Other GCP Inspections/Financial Disclosure

Two clinical sites were chosen for inspection based upon their high enrollment (sites 466, Czech Republic and 422, Belgium). However, due to the COVID-19 pandemic and associated travel restrictions present during the review cycle, in-person inspections were unable to be completed. The Agency attempted to schedule off-site inspections, but because of the pandemic, these inspections were not able to be conducted. The health authorities of these chosen sites submitted a written justification of the infeasibility of remote inspections (limited resources due to COVID-19, disallowed remote source data verification). As a result, the Office of Scientific Investigations inquired with DAI whether this sNDA could be reviewed without inspections. DAI determined that as the clinical sites did not have any concerning safety or efficacy results, it would be acceptable to proceed with review of the application without inspection of the clinical sites. In addition, during review of the original NDA, four clinical sites were inspected and no major issues were noted. 11. Advisory Committee Summary An advisory committee was not convened for this sNDA; however, CRRT dosing information is not available in any anti-infective product labeling. The scientific rationale for the addition of dosing recommendations for patients undergoing CRRT was presented at the CDER Medical Policy and Program Review Council on July 22, 2020 (see Sections 8.1 and 14.1 of this review). The Council provided a unanimous, positive opinion on the question of whether to include the dosing recommendations for the CRRT patient population in labeling.

III. Appendices

12. Summary of Regulatory History The Applicant received marketing registration for Fetroja (cefiderocol) on November 14, 2019, for the indication of treatment of complicated urinary tract infections (cUTI), including pyelonephritis in patients 18 years of age or older who have limited or no alternative treatment options. The Applicant is now seeking approval to add the hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (HABP/VABP) indications to prescribing information. Fetroja was granted both fast track and Qualified Infectious Disease Product designations on August 18, 2015, for the HABP/VABP indications. Therefore, this efficacy supplement is being reviewed on a priority review timeline. The supplemental new drug application (sNDA) was received on March 27, 2020, and has a PDUFA goal date of September 27, 2020. The IND associated with this new drug application (NDA), IND 116787, was originally received on March 22, 2013, and was deemed safe to proceed on April 17, 2013. Like the original cUTI

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Reference ID: 4676324 NDA 209445 / S-002 Cefiderocol (Fetroja) marketing application, the study conducted in support of the HABP/VABP indications was also conducted under this IND. The sNDA submission contains results of the APEKS-NP (Acinetobacter baumannii, Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumoniae, and Stenotrophomonas maltophilia in Nosocomial Pneumonia) trial, a phase 3, multicenter, randomized, parallel-group, double-blind, active-controlled noninferiority (NI) trial comparing cefiderocol to meropenem for the treatment of HABP/VABP. The trial was completed in the fall of 2019, and the Applicant requested a type B pre-sNDA meeting to discuss their plans for submission of the efficacy supplement on December 13, 2019. The meeting was granted by DAI and took place on February 24, 2020. Several key points were discussed during the meeting, namely the clinical microbiology data needed to support the inclusion of A. baumannii in the first list of clinically relevant pathogens. Given the lack of gram-negative therapy and the use of monotherapy in the APEKS-NP trial, it was agreed that additional sensitivity analyses may be required to aid in ascertaining treatment effect based on potentially confounding factors. In addition, during the pre-sNDA meeting, the Applicant informed the Division that they had in vitro minimum inhibitory concentration (MIC) data on less than 100 Achromobacter isolates but that this could be augmented with MIC values and outcome data from the compassionate use program, where Achromobacter was the third most frequent pathogen. It should be noted that postapproval, the Fetroja drug product was not readily commercially available due to manufacturing constraints, which were later resolved in February of 2020. This required care providers to obtain the drug through the compassionate use (i.e., emergency IND) program. The Division advised the Applicant to submit the compassionate use information in the sNDA but did note that the utility of this data will be limited due to being open-labeled and uncontrolled. The Applicant was also advised during the meeting that it would be necessary to provide a justification that pathogens proposed for inclusion in the second list (in vitro activity) in the Microbiology (12.4) subsection in the prescribing information are relevant to the HABP/VABP indication. An additional key point of discussion during the pre-sNDA meeting involved the determination of the susceptibility test interpretive criteria (breakpoints) and the necessity to justify these values with both clinical and animal data. The Applicant indicated during the meeting that they utilized a significant amount of in vivo animal data in their analysis. In combination with human pharmacokinetics/pharmacodynamics (PK/PD) data from plasma and an epithelial lining fluid (ELF) study, they believe they can justify their desired MIC. The Division agreed to consider this information along with the totality of other data as part of the review. The Division held an internal filing meeting for the sNDA on May 13, 2020, and the Applicant was informed on May 22, 2020, that their application would be reviewed under a priority review time frame. In addition, the Applicant was informed that no filing issues were identified and the application was filed on May 26, 2020. The PDUFA goal date is September 27, 2020.

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Reference ID: 4676324 NDA 209445 / S-002 Cefiderocol (Fetroja) 13. Pharmacology Toxicology Assessments and Additional Information

See the original review of NDA 209445 (Division of Anti-Infectives 2019). The Applicant did not submit additional nonclinical pharmacology/toxicology data in this amendment and none were necessary to support the proposed additional clinical indications. 14. Clinical Pharmacology Assessment: Additional Information

14.1. In Vitro Studies In Vitro CRRT Study (S-649266-CF-323-N) The objectives of this study are to determine cefiderocol clearance for continuous renal replacement therapy (CRRT) using an in vitro model and to identify the CRRT operational settings that could impact the clearance of cefiderocol by CRRT. In vitro CRRT was set up using a Prismaflex 7.2 control machine in continuous venovenous hemofiltration (CVVH) and continuous venovenous hemodialysis (CVVHD) modes. Bovine plasma containing potassium oxalate/sodium-fluoride was used as the vehicle in all experiments. The blood flow rate was fixed at 200 mL/min for all experiments. The study was designed to (b) (4) compare effect of CRRT mode (CVVH versus CVVHD), filter type , point of (b) (4) dilution and effluent flow rate (QE; 2 versus 4 L/h) on the determination of sieving coefficient (SC), saturation coefficient (SA), and CLCRRT. Cefiderocol was dosed to the CRRT in vitro model, which aimed to provide a mean AUC value comparable to that achieved in cUTI patients administered 2 g every 8 hours during the APEKS-cUTI trial. Serial undiluted prefilter plasma samples of cefiderocol at six time points were collected. Postfilter plasma and effluent samples of cefiderocol and urea were also collected at two time points. Table 46 summarizes all experimental conditions.

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Table 46. Summary of In Vitro CRRT Experiments

(b) (4)

Source: Table 1 from the Applicant’s study report of s-649266-cf-323-n Abbreviations: (b) (4) CRRT, continuous renal replacement therapy; CVVH, continuous venovenous hemofiltration; CVVHD, continuous venovenous hemodialysis; n/a, not applicable; (b) (4)

(b) (4)

Calculation results of cefiderocol CLCRRT from CVVH or CVVHD modes are summarized in Table 47 and Table 48, repectively.

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a Table 47. Cefiderocol CLCRRT During In Vitro CVVH as Determined by SC×Flow Rate

Source: Table 4 from the Applicant’s study report of s-649266-cf-323-n SC1, SC2, SC3, SC5 and CLTM1, CLTM2, CLTM3, CLTM4, CLTM5 represent 5 approaches to calculate sieving coefficient and clearance by CRRT, respectively, based on point of dilution (predilution, postdilution, or both) All values are presented as mean ± SD a n=2 experiments in each mode, at each flow rate, point of dilution, and filter type (24 total experiments) Abbreviations: CLTM: transmembrane clearance, which is CRRT clearance determined from in vitro model; CRRT, continuous renal replacement therapy; CVVH, continuous venovenous hemofiltration; SC, sieving coefficient; SD, standard deviation

a Table 48. Cefiderocol CLCRRT During In Vitro CVVHD as Determined by SA×Flow Rate

Source: Table 6 from the Applicant’s study report of s-649266-cf-323-n SA1, SA2 and CLTM1, CLTM2 represent 2 approaches to calculate saturation coefficient and clearance by CRRT, respectively, based on point of dilution (predilution, postdilution, or both) All values are presented as mean ± SD a n=2 experiments in each mode, at each flow rate, point of dilution, and filter type (24 total experiments) Abbreviations: CLTM: transmembrane clearance, which is CRRT clearance determined from in vitro model; CRRT, continuous renal replacement therapy; CVVHD, continuous venovenous hemodialysis; SA, saturation coefficient; SD, standard deviation The overall results of this study are summarized below: • Overall mean (±SD) % adsorption of cefiderocol to the CRRT circuit across all experiments was 10.93±6.28%. • The mean (±SD) protein binding of cefiderocol to bovine plasma was 36.1±0.04%. • The point of dilution (pre-, postdilution or both) did not make significant difference in the calculation of CLCRRT.

• There were no significant differences in the calculation of CLCRRT by SC (or SA)×QE method and by AUC method.

• CRRT mode, filter type did not affect the calculation of CLCRRT significantly.

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• However, significant mean differences were observed in CLCRRT calculated by SC/SA at 4 L/h versus 2 L/h in both CVVH (P<0.001) and CVVHD (P<0.001) modes, respectively. The significant differences in CLCRRT was observed at flow rates of 4 L/h versus 2 L/h (b) (4) (b) (4) when used (P<0.001) and filters (P<0.001), respectively.

• A linear regression equation between CLCRRT and flow rate (2 and 4 L/h) was established to be: CLCRRT =0.600 L/h+(flow rate (L/h)×0.606) We agree with the overall conclusions that CRRT mode, filter type, and point of dilution did not have significant effect on CL CRRT while QE made significant difference in the calculation of CLCRRT. However, we consider that the linear regression equation between CLCRRT and flow rate is not appropriate to be used to calculate CLCRRT. This is because that the relationship of CL CRRT and QE was established only based on two flow rates (2 and 4 L/h), which is not adequate to precisely define a linear relationship. The additional caveat of this study is the use of bovine plasma as the matrix in the experiments. This could present differences in plasma protein binding, blood/plasma drug partitioning, etc., when compared to human blood. 14.2. In Vivo Studies Intrapulmonary Pharmacokinetics Study in Ventilated Patients Being Treated for Pneumonia (Study R2117) Study R2117 was an open-label, multicenter, single-arm, phase 1b study where the primary objective was to assess the concentration of cefiderocol in ELF at steady state in hospitalized subjects with known or suspected bacterial pneumonia on treatment with standard-of-care antibiotics and requiring mechanical ventilation, and to estimate the ratio of the concentration for cefiderocol in ELF relative to plasma in these subjects. Subjects meeting eligibility criteria received 2 g of cefiderocol (or renally adjusted doses) by intravenous (IV) administration over 3 hours q8h or q6h if they had augmented renal function. Cefiderocol was to be administered for an expected minimum of three doses and up to a total of six doses in subjects with normal or augmented renal function and in subjects with mild or moderate renal impairment. For subjects with severe renal impairment a minimum of six doses up to a total of nine doses were expected. The ELF sample for determination of cefiderocol concentrations was to be collected by BAL procedure at 3, 5, or 7 hours post the start of infusion (depending on the ELF cefiderocol concentration data obtained); after administration of at least three doses of cefiderocol in subjects with normal or augmented renal function and in subjects with mild or moderate renal impairment; and after administration of at least six doses of cefiderocol in subjects with severe renal impairment. Table 49 presents plasma and ELF concentrations of cefiderocol and ELF/plasma concentration ratios from study R2117. The ELF concentrations were 3.10 to 20.7 mcg/mL at the end of infusion and 7.19 to 15.9 mcg/mL at 2 hours after the end of infusion. The geometric mean ELF/free plasma ratio was 0.212 at the end of infusion and 0.547 at 2 hours after the end of infusion based on free drug in plasma using plasma protein unbound fraction of 0.422.

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Table 49. Cefiderocol Concentrations in Plasma and ELF and ELF/Plasma Concentration Ratios From Study R2117

(b) (6)

Source: Table 2.7.2-2 from 2.7.2 Summary of Clinical Pharmacology – HABP/VABP Abbreviations: BAL, bronchoalveolar lavage; CFDC, cefiderocol; ELF, epithelial lining fluid; q8h, every 8 hours 14.3. Population PK Analyses 14.3.1. Review Summary The Applicant’s population pharmacokinetics (PPK) analysis for cefiderocol, which was to update a previously developed PPK model by including additional phase 3 data (APEKS-NP study, 1615R2132), is acceptable to support the current submission as outlined in Table 50. The Applicant’s final PPK model adequately described the observed cefiderocol plasma concentrations. Parameter estimates for the final model were estimated with acceptable precision with relative standard error (<15%) for total clearance (CL), volume of distribution in central compartment (V1), volume of distribution in peripheral compartment (V2 and V3), the intercompartmental clearance (Q2 and Q3), and covariates (creatinine clearance [CLcr] and infection site on CL, body weight, albumin [ALB] and infection on V1, and body weight on V2). The shrinkages for interindividual variability on CL and V1 were <15%. The goodness-of-fit plots showed a good agreement between the observed and the individual predicted concentrations without any obvious bias over time or predicted concentrations. The prediction- corrected visual predictive check (pcVPC) plots showed a good agreement between the observed and the simulated concentrations. The Applicant’s analyses were verified by the reviewer, with no significant discordance identified. Cefiderocol is known to be substantially excreted by the kidney. The updated PPK model identified CLcr as the most significant covariate on the PK of cefiderocol and the influence of renal function on PK was shown in the box plots for Bayesian-estimated CL by study and renal function group (Figure 6). Per the current approved labeling, dose adjustments are recommended for patients with CLcr less than 60 mL/min and for patients with CLcr 120 mL/min or greater. The Applicant’s analysis of cefiderocol Cmax and daily AUC estimated by the updated PPK model at CLcr adjusted dose regimens in the renal function groups did not show notable change from the estimates from the previous model. Based on Applicant’s analysis of plasma cefiderocol concentrations, the dose for patients with intermittent hemodialysis, continuous venovenous hemofiltration (CVVH), continuous venovenous hemodialysis (CVVHD), continuous venovenous hemodiafiltration (CVVHDF), or

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Reference ID: 4676324 NDA 209445 / S-002 Cefiderocol (Fetroja) intermittent hemodiafiltration is reasonable since their minimum of plasma concentration (13.6 mcg/mL) was higher than the target MIC of 4 mcg/mL.

Table 50. Specific Comments on Applicant’s Final Population PK model Utility of the Final Model Reviewer’s Comments Intrinsic and Intrinsic Based on a population The Applicant adequately performed extrinsic factors factor pharmacokinetic analysis, covariates assessment and evaluated the age, gender, race, AST, ALT, impact of identified covariates on BILI and ventilation do not cefiderocol PK under forward inclusion and have a statistically meaningful backward deletion criteria. Based on the effect on the estimated impacts, the review agrees with pharmacokinetics of the Applicant’s conclusions. Inclusion of cefiderocol. Meanwhile, CLcr, covariates into the base model were albumin, body weight and determined with the significance level of infection (no infection, 0.01 based on χ2 test (p<0.01, a decrease cUTI/AUP, cUTI, BSI/sepsis, in OBJ >6.64 for one degree of freedom). HAP/VAP/HCAP) have a In the stepwise backward deletion, deletion statistically significant effect of covariates from the full model was on pharmacokinetics of determined with the significance level of cefiderocol. 0.001 based on χ2 test (p<0.001, an increase in OBJ >10.83 for one degree of freedom) to construct a final model. Extrinsic factor Derive exposure Cmax, AUC The Applicant’s final model is generally metrics for acceptable for generating exposure metrics Exposure- for exposure-response analyses (Table 53). response analyses Predict exposures NA NA at alternative dosing regimen Source: Pharmacometric Review Team’s assessments and applicant’s S-649266-CPK-004 - Study Report (link). Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; AUC, area under the curve; AUP, acute uncomplicated pyelonephritis; BILI, bilirubin; BSI, bloodstream infection; cUTI, complicated urinary tract infection; Cmax, maximum plasma concentration; CLcr, creatinine clearance; HAP, hospital-acquired pneumonia; HCAP, healthcare-associated pneumonia; NA, not applicable; OBJ, objective function value,;PK, pharmacokinetics; VAP, ventilator-associated pneumonia Detailed statistical explanation of covariates was shown in Section 14.3.4. 14.3.2. Introduction The primary objectives of the Applicant’s analysis were to: • Characterize the structural PK model and quantify the population variability in the PK parameters of cefiderocol. • Describe the effects of intrinsic and/or extrinsic factors on cefiderocol exposure. • Generate individual clearance estimates for patients in phase 1, 2 and 3 studies that can be used for subsequent exposure-response analyses

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Reference ID: 4676324 NDA 209445 / S-002 Cefiderocol (Fetroja) 14.3.3. Model Development Data PPK models were developed by Applicant to describe the PK of cefiderocol (S-649266) using a total of 3855 plasma concentration data of cefiderocol from 641 subjects, from phase 1 single ascending dose/multiple ascending dose study (1203R2111) and the renal impairment study (1222R2113), the phase 2 APEKS-cUTI study (1409R2121), the phase 3 CREDIBLE-CR trial (1424R2131), and the APEKS-NP study (1615R2132). It included 92 subjects without infection, 326 patients with cUTI or acute uncomplicated pyelonephritis (AUP), 193 patients with either hospital-acquired pneumonia (HAP)/ventilator-associated pneumonia (VAP)/healthcare- associated pneumonia (HCAP), and 30 patients with BSI/sepsis. The dosing regimen and PK sampling for the clinical studies included PPK analysis were summarized in Table 51 and demographic covariates for analysis were summarized in Table 52. Table 51. Summary of Clinical Study Designs Study Dose Regimen Plasma PK Sampling Phase 1 SAD/MAD Part 1: Part 1: study for healthy Single cefiderocol 0.1-,0.25- Predose, 0.5, 1, 1.25, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, subjects in Japan , 0.5-, 1-, 2-g doses or 5, 6, 8, 10, 12, 16, 24, 36 and 48 hours from the (Study No.1203R2111; matching placebo start of the infusion PK Analysis Study No. infused over 1 hour Part 2: S-649266-CB-063-N) Part 2: Day 1 (morning dose: first dose): predose, 0.5, Multiple cefiderocol 1- 1, 1.25, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12 or 2-g doses, or matching and 16 hours placebo infused over 1 hour Days 2, 3, 5, 8 and 9 (each morning dose): q8hr for 10 days predose Day 10 (morning dose: last dose): predose, 0.5, 1, 1.25, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 16, 24, 36 and 48 hours from the start of the infusion Phase 1 renal Single cefiderocol 1-g dose Predose, 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16, impairment study in infused over 1 hour 24, 36, 48 and 72 hours from the start of the U.S. (Study No. infusion 1222R2113) Phase 2 APEKS- Cefiderocol 2-g doses Just prior to the infusion of the dose, −0.25 to 0 cUTI study for infused over 1 hour q8hr hours at the end of infusion, and 1±0.5 hours patients with cUTI with adjustments for after the end of infusion on Day 3 and AUP (Study creatinine clearance and No. 1409R2121) body size Phase 3 CREDIBLE- Cefiderocol 2-g doses Just prior to the start of infusion, 1 hour after the CR trial for patients infused over 3 hour q8hr start of infusion, at the end of infusion, and 1 with HAP/VAP/HCAP, with adjustments for eGFR hour after the end of infusion on Day 3. BSI/sepsis, or cUTI and creatinine clearance For patients with nonstable renal function (Study No. resulting in a dosing adjustment, another PK 1424R2131) sampling was performed within 24 to 72 hours after their dosing adjustment at the same timing on Day 3.

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Study Dose Regimen Plasma PK Sampling Phase 3 APEKS-NP Cefiderocol 2-g doses Just prior to the start of infusion, 1 hour after the study for patients with infused over 3 hour q8hr start of infusion, before the end of infusion, and HAP/VAP/HCAP with adjustments for eGFR 1 hour after the end of infusion on Day 3 or Day (Study No. and creatinine clearance 4. 1615R2132) For patients with nonstable renal function resulting in a dosing adjustment, another PK sampling was performed within 24 to 72 hours after their dosing adjustment at the same timing as above. Source: Applicant’s S-649266-CPK-004 - Study Report, Table T1 on Page 16 (link). Abbreviations: AUP, acute uncomplicated pyelonephritis; BSI, bloodstream infection; cUTI, complicated urinary tract infection; eGFR, estimated glomerular filtration rate; HAP, hospital-acquired pneumonia; HCAP, healthcare-associated pneumonia; MAD, multiple ascending dose; OBJ: objective function value,;PK, pharmacokinetics; SAD, single ascending dose; VAP, ventilator- associated pneumonia Table 52. Summary of Baseline Demographic Covariates for Analysis

Source: Applicant’s S-649266-CPK-004 - Study Report, on Page 43 (link). a Number of subjects (percentage of all subjects) Abbreviations: AUP, acute uncomplicated pyelonephritis; BSI, bloodstream infection; CrCL, creatinine clearance calculated by Cockcroft-Gault equation; cUTI, complicated urinary tract infection; eGFRabs, absolute estimated glomerular filtration rate; eGFRadj, body-surface-area-adjusted estimated glomerular filtration rate; HAP, hospital-acquired pneumonia; HCAP, healthcare- associated pneumonia; SD, standard deviation; VAP, ventilator-associated pneumonia Base Model The base model was a three-compartment PK model with infusion and first-order elimination from the central compartment for healthy subjects, subjects with various renal functions, and patients with HAP/VAP/HCAP, BSI/sepsis, or cUTI/AUP. The three-compartment model included the following parameters: CL, V1, V2, V3, Q2, and Q3. Interindividual variability was modelled assuming a log-normal distribution for patient level random effects. The interindividual variability was considered for CL, V1, Q2, and V2 since the interindividual variability for V3 and Q3 was not estimable for the data in healthy volunteers and subjects with various renal functions. Furthermore, the data obtained with the sparse sampling in the phase 2 study (1409R2121) and phase 3 studies (1424R2131 and 1615R2132) were not expected to be informative for the interindividual variability relevant to the three compartmental parameters. 94 Integrated Review Template, version date 2019/10/16

Reference ID: 4676324 NDA 209445 / S-002 Cefiderocol (Fetroja) Intraindividual variability was tested as proportional or combination error model (the additive error + the proportional error model) on the dependent variable. Model evaluation and selection were based on the point estimates of PK parameters, their respective relative standard errors and standard statistical criteria of goodness-of-fit, such as a decrease in the minimum objective function value, accuracy of parameter estimation (i.e., 95% CI excluding 0) by bootstrap, successful model convergence, and diagnostic plots (pcVPC). Covariate Analysis Covariate parameters, including CLcr, body weight, age, sex, ALB AST, ALT, bilirubin (BILI), race, infection, and ventilation were tested on CL, and body weight, age, sex, ALB, race, infection, and ventilation were tested as a covariate on V1. In addition body weight was tested as a covariate on other PK parameters (Q2 and V2). Covariates (power model, piece-wise linear model, power + linear combination model, and multiplicative model) were assessed for covariates with forward selection criteria of the significant level of 0.01 based on χ2 test (p<0.01, a decrease in OBJ >6.64 for one degree of freedom) and backward deletion criteria with the significance level of 0.001 based on χ2 test (p<0.001, an increase in OBJ >10.83 for one degree of freedom) 14.3.4. Final Model The parameter estimates for the final PPK model are listed in Table 53. The goodness-of-fit plots for the final covariate model for all data are shown in Figure 4. The pcVPC plot for the final covariate model with all data is shown in Figure 5. The structural model for the final PPK model was a three-compartmental model as parameterized with CL, V1, V2, V3, Q2, and Q3 for cefiderocol. An exponential error model was used for interindividual variability, and a proportional error model was used for intra-individual variability. CLcr and infection site on CL, body weight, ALB, infection on V1, and body weight on V2 were identified as significant covariates and included in the final model: • CLcr was the most significant covariate on the PK of cefiderocol (see Section 14.3.5 for details) • Infection with cUTI/AUP, BSI/sepsis, or HAP/VAP/HCAP was a significant covariate on CL and V1 in the final model. The final model suggested CL in patients with cUTI/AUP in the phase 2 study was 27% higher than that in subjects without infection. CL in patients were 13% lower for the cUTI in the CREDIBLE-CR trial, 8% higher for BSI/sepsis, or 2% lower for HAP/VAP/HCAP than that in subjects without infection. The final model also suggested V1 in patients with infection was 39% higher than that in subjects without infection. • A negative correlation between ALB and V1 was observed. The median of ALB for patients in the CREDIBLE-CR and APEKS-NP studies were 2.7 and 3.0 g/dL, respectively, and lower than that for subjects in the phase 1 and phase 2 studies (4.2 g/dL). • Body weight was a significant covariate on V1 and V2 with a power model with exponent of 0.58.

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Table 53. Population Pharmacokinetic Parameter Estimates for the Final Model

Source: Applicant’s S-649266-CPK-004 - Study Report, Table 5 on page 48 (link). a CrCL <150 mL/min; CL =4.04*(CrCL/83.0)0.682 * (1.27 for patients with cUTI/AUP in phase 2 cUTI study) * (0.872 for patients with cUTI in phase 3 CREDIBLE-CR trial) * (1.08 for patients with BSI/sepsis) * (0.981 for patients with HAP/VAP/HCAP) a (cont.) CrCL ≥150 mL/min; CL =4.04*(150/83.0)0.682 * (1.27 for patients with cUTI/AUP in phase 2 cUTI study) * (0.872 for patients with cUTI in phase 3 CREDIBLE-CR trial) * (1.08 for patients with BSI/sepsis) * (0.981 for patients with HAP/VAP/HCAP) V1=7.78 * (body weight/72.6)0.580 * (a bumin/3.9)-0.617 * (1.39 for patients with infection) V2=5.77 * (body weight/72.6)0.580 Abbreviations: AUP, acute uncomplicated pyelonephritis; BSI, bloodstream infection; CI, confidence interval; CrCL, creatinine clearance calculated by Cockcroft-Gault equation; cUTI, complicated urinary tract infection; CV, coefficient of variation; HAP, hospital-acquired pneumonia; HCAP, healthcare-associated pneumonia; sh_ηp, shrinkage in the standard deviation of interindividual variability parameters η; sh_ε, shrinkage in the standard deviation of intra-individual variability parameters ε; %RSE, relative standard error in percent; R, coefficient of correlation; VAP, ventilator-associated pneumonia

Figure 4. Goodness-of-Fit Plots for Final Covariate Model

Source: Applicant’s S-649266-CPK-004 - Study Report, Figure 10 on Page 84-85(link).

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Figure 5. pcVPC Plots for Final Covariate Model

(Figure 5 cont. on the next page)

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Source: Applicant’s S-649266-CPK-004 - Study Report, Figure 15 on Page 100-101 (link). Solid line: observed median. Dashed line: observed 2.5th and 97.5th percentiles. Dark grey shaded area: model predicted 95% CI of median. Grey shaded area: model predicted 95% CIs of 2.5th and 97.5th percentiles. 500 simulations Abbreviations: ESRD, end stage renal disease; pcVPC, prediction-corrected visual predictive check 14.3.5. Effect of Renal Function Cefiderocol is known to be substantially excreted by the kidney. Similar to the previously developed model, the updated PPK model identified CLcr as the most significant covariate on the PK of cefiderocol, and time-varying CLcr was a better predictor than baseline CLcr in phase 3 studies. The influence of renal function to PK is shown in the box plots for Bayesian-estimated CL by study and renal function group (Figure 6). The daily AUC values at the dose regimen adjusted by CLcr (Table 54) were summarized by different renal function groups and study (Table 55). At the dose regimen adjusted by CLcr, the ratios of geometric mean daily AUC in the augmented or impaired renal function groups relative to the normal renal function group ranged from 0.92 to 1.44 in the APEKS-NP study and from 0.74 to 1.22 in the CREDIBLE-CR trial.

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Table 54. Renal Function Groups and Adjusted Dose Regimens Dose Regimens With Renal Function Group CLcr (mL/min) 3-hr Infusion Augmented renal function >120 2 g q6hr Normal renal function 90 to <120 2 g q8hr Mild renal impairment 60 to <90 2 g q8hr Moderate renal impairment 30 to <60 1.5 g q8hr Severe renal impairment 15 to <30 1 g q8hr ESRD 5 to <15 0.75 g q12hr Source: Applicant’s S-649266-CPK-004 - Study Report, Table T2 on Page 27 (link). Abbreviations: CLcr, creatinine clearance; ESRD, end-stage of renal disease; q6hr, every 6 hours; q8hr, every 8 hours; q12hr, every 12 hours

Figure 6. Box Plots for Bayesian-Estimated CL by Study and Renal Function Group

Source: Applicant’s S-649266-CPK-004 - Study Report, Figure 17 on Page 102 (link). Abbreviations: CL, clearance; ESRD, end-stage of renal disease;

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Table 55. Summary of Post hoc Estimates of Daily AUC at CrCL-Adjusted Dose Regimens by Study and Renal Function Group for Patients With Infection

Source: Applicant’s S-649266-CPK-004 - Study Report, Table 9 on Page 52 (link). a Geometric mean (CV%) Abbreviations: AUC, area under the curve; AUP, acute uncomplicated pyelonephritis; BSI, bloodstream infection; CrCL, creatinine clearance calculated by Cockcroft-Gault equation; cUTI, complicated urinary tract infection; CV, coefficient of variation; ESRD, end- stage renal disease; HAP, hospital-acquired pneumonia; HCAP, healthcare-associated pneumonia; VAP, ventilator-associated pneumonia 14.3.6. Comparison of Pharmacokinetics Between Patients With and Without Hemodialysis The Applicant graphically evaluated the effect of intermittent hemodialysis, CVVH, CVVHD, CVVHDF and intermittent hemodiafiltration on the exposures of cefiderocol. As shown in Figure 7, the plasma cefiderocol concentrations for the patients with intermittent hemodialysis, CVVH, CVVHD, CVVHDF, or intermittent hemodiafiltration were within the range of plasma concentrations for the patients without these treatments. The Applicant reported that the minimum of plasma concentration of cefiderocol for the patients with hemodialysis was 13.6 mcg/mL (5.74 mcg/mL as free cefiderocol plasma concentration), which was higher than the target MIC of 4 mcg/mL. The study suggested that adequate exposure to cefiderocol was achieved at the selected dose regimen for the patients with intermittent hemodialysis, CVVH, CVVHD, CVVHDF, or intermittent hemodiafiltration.

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Figure 7. Observed Plasma Cefiderocol Concentration Profiles for Patients With or Without Hemodialysis in CREDIBLE-CR Trial

Source: Applicant’s S-649266-CPK-004 - Study Report, Figure 33 on Page 118 (link). Abbreviations: CVVH, continuous venovenous hemofiltration; CVVHD, continuous venovenous hemodialysis; CVVHDF, continuous venovenous hemodiafiltration; HD, hemodialysis. 15. Trial Design: Additional Information and Assessment

The following is the protocol synopsis dated February 22, 2019, as submitted in the complete study report dated January 24, 2020, for the APEKS-NP trial. Additional details and commentary on the trial design are provided after the synopsis. Synopsis Study title: A Multicenter, Randomized, Double-blind, Parallel-group, Clinical Study of S- 649266 Compared with Meropenem for the Treatment of Hospital-acquired Bacterial Pneumonia, Ventilator-associated Bacterial Pneumonia, or Healthcare-associated Bacterial Pneumonia Caused by Gram-negative Pathogens Study number: 1615R2132 Study phase: 3 Primary objective: • To compare all-cause mortality (ACM) at day 14 of subjects who receive S-649266 with that of subjects who receive the comparator, meropenem, in adults with HABP,VABP, or healthcare-associated bacterial pneumonia (HCABP) caused by gram-negative pathogens 101 Integrated Review Template, version date 2019/10/16

Reference ID: 4676324 NDA 209445 / S-002 Cefiderocol (Fetroja) Secondary objectives: Key secondary objectives: • To compare the clinical outcome of treatment with S-649266 with that of meropenem in subjects at test-of-cure (TOC)1 • To compare the microbiologic outcome of treatment with S-649266 with that of meropenem at TOC • To compare day 14 ACM of S-649266 with that of meropenem for superiority of S- 649266 Other secondary objectives: Efficacy: • To compare the clinical outcome of treatment with S-649266 with that of meropenem in subjects at early assessment (EA),2 end of treatment (EOT),3 and follow-up (FU) • To compare the microbiologic outcome of treatment with S-649266 with that of meropenem at EA, EOT, and FU • To compare the ACM at day 28 of subjects treated with S-649266 with that of subjects treated with meropenem • To compare the ACM during treatment and the FU period (until end of study [EOS])4 of S 649266 with that of meropenem • To compare the resource utilization required for the two study treatments for the study- qualifying infection. This endpoint will not be included in the clinical study report, but it will be analyzed based upon a separate analytical plan after the conclusion of the study Safety: • To assess the safety of S-649266 Study design: This is a phase 3, multicenter (multinational), double-blind, parallel-group, randomized, active- controlled study in approximately 300 subjects with documented nosocomial pneumonia (NP) caused by gram-negative bacteria. Subjects meeting eligibility criteria and assessed by the investigator as requiring 7 to 14 days of IV treatment in the hospital will be randomized (1:1) to either S-649266, 2 g, administered intravenously over 3 hours every 8 hours (q8h), or to meropenem, 2 g, administered intravenously over 3 hours, q8h. Linezolid will be administered for at least 5 days to subjects in both arms to provide coverage for methicillin-resistant Staphylococcus aureus and to maintain the study blind and in the S-649266 arm to provide coverage for gram-positive bacteria.

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Reference ID: 4676324 NDA 209445 / S-002 Cefiderocol (Fetroja) Study population: Subjects with documented NP caused by a suspected gram-negative pathogen(s) will be enrolled. Key inclusion criteria: Subjects who fulfill the following criteria at Screening will be included in the study: • Subjects 18 years or older at the time of signing informed consent. • Subjects who have provided written informed consent or their informed consent has been provided by a legally authorized representative (Note: Country-specific rules and local ethics committee approval for legally authorized representative informed consent will determine whether or not and how a subject unable to comprehend or sign the informed consent is allowed to be enrolled in the study). • Subjects who meet the clinical diagnosis criteria for HABP/VABP/HCABP. • All subjects must fulfill at least one of the following clinical criteria at screening: — New onset or worsening of pulmonary symptoms or signs, such as cough, dyspnea, tachypnea (e.g., respiratory rate >25 breaths/minute), expectorated sputum production, or requirement for mechanical ventilation.

— Hypoxemia (e.g., a partial pressure of oxygen [PaO2] <60 mm Hg while the subject is breathing room air, as determined by arterial blood gas [ABG], or worsening of the ratio of the PaO2 to the fraction of inspired oxygen [PaO2/FiO2]). — Need for acute changes in the ventilator support system to enhance oxygenation, as determined by worsening oxygenation (ABG or PaO2/FiO2) or needed changes in the amount of positive end-expiratory pressure. — New onset of or increase in (quantity or characteristics) suctioned respiratory secretions, demonstrating evidence of inflammation and absence of contamination. • All subjects must have at least one of the following signs: — Documented fever (i.e., core body temperature [tympanic, rectal, esophageal] ≥38°C [100.4°F], oral temperature ≥37.5°C, or axillary temperature ≥37°C). — Hypothermia (i.e., core body temperature [tympanic, rectal, esophageal] ≤35°C [95.0°F], oral temperature ≤35.5°C, and axillary temperature ≤36°C). — Leukocytosis with a total peripheral white blood cell (WBC) count ≥10,000 cells/mm3. — Leukopenia with total peripheral WBC count ≤4500 cells/mm3. — Greater than 15% immature neutrophils (bands) noted on peripheral blood smear. • All subjects must have a chest radiograph during screening or have a previous chest radiograph within 48 hours prior to randomization showing the presence of new or progressive infiltrate(s) suggestive of bacterial pneumonia. A computed tomography (CT) scan in the same time window showing the same findings could also be acceptable. • All subjects must have a suspected gram-negative infection involving the lower respiratory tract by one or more of the following: 103 Integrated Review Template, version date 2019/10/16

Reference ID: 4676324 NDA 209445 / S-002 Cefiderocol (Fetroja) — Gram stain of lower respiratory secretions showing gram-negative bacteria, either alone or mixed with gram-positive bacteria at or within 72 hours prior to randomization. — Microbiologic culture of respiratory tract secretions within 72 hours prior to randomization identifying gram-negative aerobic bacteria. — Other diagnostic tests, including molecular tests, which provide evidence of gram- negative bacterial infection of the lower respiratory tract. — Pneumonia highly suspected to be due to gram-negative bacteria based on prior antibiotic use or local epidemiologic evidence of gram-negative infection outbreak. • Subject is male (no contraception required) or female and meets one of the following criteria: — Surgically sterile (has had a hysterectomy and/or bilateral oophorectomy, or a bilateral salpingectomy or tubal ligation for the purpose of contraception for at least 6 weeks with appropriate documentation of such surgery). — Postmenopausal (defined as older than 45 years of age with cessation of regular menstrual periods for at least 6 months and a follicle-stimulating hormone level of >40 mIU/mL, or amenorrhea for at least 12 months). — Of childbearing potential and using combined (estrogen and progestogen) or progestogen-only hormonal contraception associated with inhibition of ovulation (including oral, intravaginal, injectable, implantable, and transdermal contraceptives), or an intrauterine device, or intrauterine hormone-releasing system for the entire duration of the study. — Of childbearing potential and practicing abstinence as a preferred and usual life style and agrees to continue practicing abstinence from screening for the entire duration of the study. — Of childbearing potential and whose sole heterosexual partner has been successfully vasectomized and agrees to not have other heterosexual partners for the entire duration of the study. • Subjects who failed empiric therapy will be allowed in this study. However, confirmation of both clinical and microbiological failure is necessary. — Clinical failure: An investigator needs to confirm clinical failure of empiric treatment by clinically available information such as vital signs, physical examinations, laboratory data, and/or imaging. — Microbiological failure: Respiratory specimens from a subject need to meet either of the following: . The lower respiratory tract specimen taken at the time of or before empiric therapy shows that the pathogen cultured is a gram-negative aerobic bacteria, and the pathogens are resistant or intermediate to all the empiric antibiotics used.

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Reference ID: 4676324 NDA 209445 / S-002 Cefiderocol (Fetroja) . The pathogen from a specimen obtained after at least 2 calendar days of the empiric antibiotic regimen demonstrates that it is a gram-negative aerobe, or shown in Gram stain as gram-negative bacteria. Exclusion criteria: Subjects who meet any of the following criteria at screening will be excluded from the study: • Subjects who have known or suspected community-acquired bacterial pneumonia, atypical pneumonia, viral pneumonia, or chemical pneumonia (including aspiration of gastric contents, inhalation injury). • Subjects who have a history of any hypersensitivity to cephalosporins or to carbapenems, or severe hypersensitivity to any other type of β-lactams other than cephalosporins and carbapenems (e.g., penicillins, monobactams), or hypersensitivity to linezolid (Note: For β-lactams, a history of a mild rash followed by uneventful re-exposure is not a contraindication to enrollment). • Subjects with a gram-negative infection caused by a carbapenem-resistant pathogen, if known at the time of randomization (Note: Subjects who have a carbapenem-resistant pathogen identified after randomization should be evaluated clinically before discontinuation of study treatment). • Subjects with coinfection caused by invasive aspergillosis, mucormycosis, or other highly lethal mold. • Subjects who have central nervous system infection (e.g., meningitis, brain abscess, shunt infection). • Subjects with cystic fibrosis. • Subjects in refractory septic shock, defined as persistent hypotension despite adequate fluid resuscitation or despite vasopressive therapy at the time of randomization. • Subjects with neutropenia (i.e., polymorphonuclear neutrophils <500 cells/mcL). • Female subjects who have a positive pregnancy test at screening, who are lactating, or who refuse to use one of the previously specified methods of contraception. • Subjects with an APACHE II score of >35. • Subjects who have received potentially effective antibiotic therapy for a continuous duration of more than 24 hours during the previous 72 hours prior to randomization (Note: Subjects failing empiric therapy as defined in inclusion criterion 9 may be eligible for inclusion). • Subjects with any condition or circumstance that, in the opinion of the investigator, would compromise the safety of the subject or the quality of the study data. • Subjects receiving peritoneal dialysis (hemofiltration and hemodialysis are permitted). • Subjects requiring continued treatment with methotrexate, procainamide, probenecid, monoamine oxidase inhibitors, or valproic acid.

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Reference ID: 4676324 NDA 209445 / S-002 Cefiderocol (Fetroja) • Subjects who have received another investigational drug or device within 30 days prior to study entry. • Subjects who have previously been randomized in this study or have previously received S-649266. • Subjects with one or more of the following laboratory abnormalities in baseline specimens: AST, ALT, ALP, or total BILI level >3 times the upper limit of normal (ULN), platelet count <40,000/mcL • Subjects with bronchiectasis with symptoms of persistent or recurrent bronchial infection related to irreversibly damaged and dilated bronchi; namely, subjects with clinical bronchiectasis. • Subjects with lung abscesses. Test drug, dose, and mode of administration: S-649266 (cefiderocol), 2 g, is to be administered intravenously q8h as a 3-hour infusion in subjects with normal renal function. Dose adjustment for renal function or dialysis is required, and the dosages established by clinical testing are presented in the protocol. The solution volume for infusion must be at least 100 mL. Control treatment, dose, and mode of administration: The control population will be treated with meropenem. The dosing regimen will be 2 g as a 3- hour infusion q8h. Dosage adjustment for renal function is required. The solution volume for infusion must be at least 100 mL. Concomitant linezolid treatment, dose, and mode of administration: Linezolid 600 mg will be administered intravenously every 12 hours (q12h) over 30 minutes to 2 hours concomitantly to provide coverage for gram-positive bacteria in the S-649266 arm, to provide coverage for methicillin-resistant S. aureus (MRSA) in both study arms, and to maintain the study blind. Linezolid can be discontinued after 5 days if a subject’s lower respiratory tract specimens do not provide evidence of gram-positive infection when appropriate lower respiratory tract specimens have been obtained, and the subject is not at high risk for MRSA infection (e.g., no prior known MRSA colonization in the lower airway, no prior MRSA pneumonia in the past 6 months, or low prevalence (<10% to 20%) of MRSA in the healthcare facility, etc.). If a subject’s lower respiratory tract specimens demonstrate gram-positive infection, if respiratory specimens have not been obtained, or if a subject is at high risk for MRSA infection, then linezolid should be administered for the entire treatment period of 7 to 14 days along with S-649266 or meropenem. Duration of treatment: The treatment duration for S-649266 or meropenem is anticipated to be 7 to 14 days, which is consistent with published treatment guidelines for HABP/VABP/HCABP infections. Based on the investigator’s clinical assessment of the subject and a clear reason being documented in the electronic case report form, treatment may be extended up to 21 days. All study treatments are to be administered in the hospital.

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Reference ID: 4676324 NDA 209445 / S-002 Cefiderocol (Fetroja) Prohibited concomitant therapy: • Systemic antibiotics, other than linezolid, meropenem, and S-649266, are not permitted from randomization until TOC. • Aerosolized antibiotics are not permitted from randomization until after TOC. • Probenecid, methotrexate, procainamide, monoamine oxidase inhibitors, and valproic acid are not permitted from screening until EOT. Efficacy assessment: In addition to the 14-day ACM (primary efficacy endpoint), both clinical and microbiological outcomes will be assessed by the investigator at EA, EOT, TOC, and FU. If case study treatment duration is extended beyond 14 days, an additional clinical and microbiological outcome will be assessed on day 14. Pharmacokinetic assessments: All subjects will have blood drawn for sparse sampling of plasma concentrations of S-649266 for PK assessment. PK blood sampling will preferably be performed on day 3 or 4. The following is the schedule for the sampling time points: (1) Just prior to the start of the 3-hour infusion (2) 1 hour after the start of infusion (3) Before the end of infusion (4) 1 hour after the end of infusion The actual sampling date and time will be recorded. The PK sampling will be repeated when/if the drug dosage was changed due to changes in renal function determined at EA; this should occur 24 to 72 hours after the change in dosing regimen. In the case of premature EOT, a single blood sampling should be performed, if possible, as soon as possible at EOT (within 24 hours), which is defined as receiving <7 days of IV treatment with either S-649266 or meropenem. Safety assessments: Subject safety will be assessed from the time of having signed informed consent to the end of the study by identifying TEAEs with the addition of physical and laboratory evaluations, which include multiple electrocardiograms obtained early in the treatment with study drug. In case treatment duration is extended beyond 14 days, additional safety assessments will be conducted on day 14. Safety surveillance will extend up to 28 days after the last dose of the drug treatment. Statistical methods: For the primary efficacy endpoint, the adjusted estimates of the difference in the ACM at day 14 between S-649266 and meropenem will be presented along with 95% CIs based on a stratified analysis using Cochran-Mantel-Haenszel (CMH) weights. The CI will be two-sided. The CMH weights will be calculated with the stratification factor: APACHE II score (≤15 and ≤16).

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Reference ID: 4676324 NDA 209445 / S-002 Cefiderocol (Fetroja) Sample size: The study design and the primary objective are based on a 12.5% NI margin to exclude the possibility that S-649266 is more than 12.5% inferior to meropenem for the endpoint of ACM at day 14. A sample size of 244 evaluable subjects (122 evaluable subjects in the S-649266 group and 122 evaluable subjects in the meropenem group) is required to have 90% power with a one-sided significance level of 0.025 assuming a 10% ACM rate at day 14 in both groups with a 12.5% NI margin. It is further estimated that approximately 20% of randomized subjects will be nonevaluable, and therefore excluded from the primary population, because they have not received any doses of a study drug treatment, or because they had a bacterial pneumonia caused by anaerobic and/or gram-positive aerobic bacteria only. Therefore, it is expected that it will be necessary to randomize up to 300 subjects. The nonevaluable rate will be assessed based on a blinded estimate performed after approximately 150 subjects are enrolled, and the randomized population size may be adjusted to meet study requirements. Additionally, the Applicant will conduct a blinded evaluation of ACM after approximately 150 subjects are enrolled and may perform a blinded re-estimation of sample size if deemed necessary. Stratification at randomization: Randomization will be performed by the stratified randomization method using the infection diagnosis (HABP/VABP/HCABP) and APACHE II score (≤15 and ≤16) as allocation factors. Safety and efficacy evaluation: When approximately 50 and 150 subjects have completed treatment and the FU visit, an evaluation of safety and efficacy data will be performed by the Data Safety Monitoring Board (DSMB) according to the DSMB charter. After the review, the DSMB will communicate their recommendation(s) to the Applicant. Number of study sites/countries: It is estimated that approximately 135 study sites from around the world will participate in this clinical study. Study duration: Study duration for individual subjects: approximately 5 to 7 weeks Planned duration of the study: approximately 26 months (24 months for enrollment and 5 to 7 weeks to complete the study) Date of original (Version 1): August 2, 2016 Date of latest amendment: February 22, 2019 We now provide additional details and commentary on the trial design. Changes to the Protocol and Statistical Analysis Plan The first subject was recruited on October 24, 2017, and the final subject completed study participation on April 1, 2019. A number of changes were made to the protocol and statistical analysis plan after the initiation of the trial, with the final set of changes to both protocol and statistical analysis plan made on February 22, 2019. No important changes to either protocol nor

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Reference ID: 4676324 NDA 209445 / S-002 Cefiderocol (Fetroja) statistical analysis plan were made prior to this final set of changes, which occurred after both DSMB-conducted interim analyses. The major changes made in the final set were: • Two-sided p-values were to be used for testing NI and superiority of the primary and key secondary endpoints. • In prior versions of the protocol, the unblinded DSMB looked at efficacy and safety data were not considered interim analyses. In the final protocol, they were considered interim analyses, with an alpha spend of 0.0001 to be used to control alpha at each interim analysis. It appears that formal efficacy analyses were not conducted at the interim analyses. • Clarification that systematic antibiotics for gram-negative infections, other than the two study drugs, were not permitted from randomization until the TOC visit. • If a subject withdrew from the study, the investigator was to attempt to collect TEAE information through the planned EOS. In addition, major nonfatal TEAEs was to be evaluated at days 14 and 28. Interim Analyses As noted in the protocol synopsis, an independent DSMB was to perform unblinded reviews of safety and efficacy data, and results of the interim analyses were not to be shared with the Applicant. The DSMB could recommend continuing, stopping, or modifying the study. In addition, after about 150 subjects were enrolled: (i) the rate of subjects included in the modified intention-to-treat (mITT) population was to be assessed based on a blinded estimate, and (ii) a blinded estimation of the rate of ACM was to be performed. Either could lead to an adjustment in sample size. Cochran-Mantel-Haenszel Stratum-Weighted Estimator In analyzing binary endpoints ACM, microbiological outcome, and clinical outcome at different time points, the Applicant specified using the CMH stratum-weighted estimator to estimate between-arm differences in mortality/treatment success rates, to construct CIs, to and test hypotheses. This estimator estimates the difference in rates within predefined strata and then computes a weighted average of the strata-specific differences to obtain a population-wide estimate of the between-arm difference in rates. For ACM endpoints, two strata were specified, in terms of high versus low baseline APACHE II scores. For microbiological and clinical outcomes, six strata were specified by crossing high versus low baseline APACHE II scores with diagnosis at baseline (HABP, VABP, HCABP). The CMH stratum-weighted estimator consistently estimates the population-level between-arm difference in rates and hence is a valid estimation method. Handling Missing and Indeterminate Data We discuss how missing and indeterminate data were handled with regard to the ACM, clinical outcome, and microbiological outcome endpoints. • ACM at days 14/28: If a subject withdraws from the study prior to day 14/28, then, per the Applicant, ACM at that time point is considered missing and the subject is ignored in efficacy analyses of ACM at that time point. That is, per the Applicant, efficacy analyses of ACM are complete case analyses.

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Reference ID: 4676324 NDA 209445 / S-002 Cefiderocol (Fetroja) • Clinical outcome and microbiological outcome at EA/EOT/TOC: Per the Applicant, subjects lost to FU or who had missing or indeterminate outcomes were considered treatment failures. Strictly speaking, values coded as “indeterminate” were not necessarily missing values. For example, subjects who died from causes other than pneumonia had postdeath clinical outcome values coded as “indeterminate.” Given how indeterminate values were handled for clinical outcome, however, such subjects were treated as clinical failures. The Applicant’s analyses of ACM endpoints were not intention-to-treat (ITT) analyses as they only included subjects with complete data rather than including all subjects in the mITT population. ITT sensitivity analyses for these endpoints are presented in Section 16. 16. Efficacy Assessment Additional Information and Assessment

This section provides additional analyses of the key efficacy endpoints, including sensitivity analyses of the primary endpoint and subgroup analyses. The results reported here are consistent with the results reported in Section 6. In addition, missing and indeterminate data rates are examined and the results of interim analyses are discussed. Missing and Indeterminate Data Rates The following table presents the amount of missing or indeterminate data, by arm, for the key endpoints. The two ACM endpoints have negligible amounts of missing data in both arms. Almost one third of subjects had indeterminate values on microbiological outcome at TOC, with the indeterminate proportion roughly equal in the two arms. Rates of indeterminate values in clinical outcome at TOC were roughly half of those for microbiological outcome at TOC, with the cefiderocol arm having 4.4% more indeterminacy than the meropenem arm.

Table 56. Amount of Missing or Indeterminate Data in Key Endpoints in the mITT Population, APEKS-NP Trial Endpoint Cefiderocol Meropenem ACM at day 14 0/145 (0.0) 1/147 (0.7) ACM at day 28 2/145 (1.4) 1/147 (0.7) Microbiological outcome at TOC 39/124 (31.5) 39/127 (30.7) Clinical outcome at TOC 24/145 (16.6) 18/147 (12.2) Source: adsl.xpt. All values are expressed as n/N’ (%). The cefiderocol arm included 145 subjects; the meropenem arm included 147 subjects. Abbreviations: ACM, all-cause mortality; mITT, modified intention-to-treat; n, number of subjects with missing or indeterminate date; N’, number of subjects for whom the endpoint is defined; TOC, test-of-cure Interim Analyses’ Results Unblinded interim analyses of safety and efficacy data, to be conducted by the DSMB, were scheduled for when 50 and then 150 subjects had completed treatment and at FU. At the first interim analysis, the decision was made to continue the trial as planned but to hold a second interim analysis when 100 subjects had completed treatment and at FU. At this interim analysis, the decisions were made to again continue the trial as planned and to cancel the interim analysis at 150 subjects. A third interim analysis was conducted when all subjects had completed treatment and at FU, prior to the official conduct of efficacy and safety analyses. At each of the

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Reference ID: 4676324 NDA 209445 / S-002 Cefiderocol (Fetroja) three interim analyses, alpha =0.0001 was used for testing efficacy-related hypotheses. In addition, the blinded sample size re-estimation after recruitment of about 150 subjects led to the decision to maintain the planned sample size rather than increase it. Use of standard methods of estimation and CI construction in trials with group sequential designs can lead to biased estimates and CIs that do not achieve their nominal coverage rates. We conducted a simulation study to examine whether standard methods sufficed for this trial. The study showed that standard point estimates were nearly unbiased and CIs achieved their nominal coverage rates. Therefore, special statistical methods for estimation and CI construction were not needed. Additional Efficacy Results Additional Analyses for All-Cause Mortality We first present two sensitivity analyses that examine the consequences of handling unknown survival status differently than the Applicant did. The Applicant excluded subjects with unknown status from its ACM analyses, which were presented in Section 6. One alternative approach is the “worst-case” handling of missing endpoint data, which imputes values in a way that maximally disadvantages cefiderocol in its comparison with meropenem: missing values in the cefiderocol arm are imputed as treatment failures and missing values in the meropenem arm are imputed as treatment successes. Another alternative approach, more commonly used than excluding subjects, is to consider subjects with missing endpoint values as treatment failures (regardless of which arm they belong to). Note that both alternative approaches produce ITT analyses, as they include all subjects in the primary analysis population. The following two tables present the results of analyses of ACM at 14 and 28 days using the alternative approaches to handling missing data described above. The key takeaway from these tables is that cefiderocol is noninferior to meropenem even using alternative missing data handling. The overall results presented are similar to the Applicant’s complete case results, as would be expected given the paucity of unknown survival status. Table 57. All-Cause Mortality at Days 14 and 28 in the mITT Population With “Worst-Case” Handling of Missing Data, APEKS-NP Trial Endpoint Cefiderocol Meropenem Difference % (CI) ACM at day 14 18/145 (12.4) 17/147 (11.6) 0.9 (-6.5, 8.3)a ACM at day 28 32/145 (22.1) 30/147 (20.4) 1.7 (-7.5, 11.0) Source: adsl.xpt. All values in the cefiderocol and meropenem columns are expressed as n/N’ (%). Estimates of difference in mortality rates and construction of confidence intervals derived from use of Cochran-Mantel-Haenszel (CMH) stratum-weighted estimator, with strata based on APACHE II score at randomization (<=15 vs. >=16). 95.04% (rather than 95%) confidence intervals are reported, per adjustment in alpha level due to performance of multiple interim analyses. The cefiderocol arm included 145 subjects; the meropenem arm included 147 subjects. For ACM at day 14, 0 cefiderocol subjects and 1 meropenem subject had unknown survival status; for ACM at day 28, 2 cefiderocol subjects and 1 meropenem subject had unknown survival status. a The null hypothesis that cefiderocol is inferior to meropenem (with respect to the 12.5 noninferiority margin) was rejected, 2-sided p =0.002. No hypothesis tests were performed with respect to ACM at day 28. Abbreviations: ACM, all-cause mortality; APACHE, Acute Physiology and Chronic Health Evaluation; CI, confidence interval; mITT, modified intention-to-treat; n, number of subjects who died by the indicated timepoint; N’, number of subjects in the mITT population of treatment arm

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Table 58. All-Cause Mortality at Days 14 and 28 in the mITT Population With Unknown Survival Status Treated as Death, APEKS-NP Trial Endpoint Cefiderocol Meropenem Difference % (CI) ACM at day 14 18/145 (12.4) 18/147 (12.2) 0.2 (-7.2, 7.7)a ACM at day 28 32/145 (22.1) 31/147 (21.1) 1.1 (-8.2, 10.4) Source: adsl.xpt. All values in the cefiderocol and meropenem columns are expressed as n/N’ (%). Estimates of difference in mortality rates and construction of confidence intervals derived from use of Cochran-Mantel-Haenszel (CMH) stratum-weighted estimator, with strata based on APACHE II score at randomization (<=15 vs. >=16). 95.04% (rather than 95%) confidence intervals are reported, per adjustment in alpha level due to performance of multiple interim analyses. The cefiderocol arm included 145 subjects; the meropenem arm included 147 subjects. For ACM at day 14, 0 cefiderocol subjects and 1 meropenem subject had unknown survival status; for ACM at day 28, 2 cefiderocol subjects and 1 meropenem subject had unknown survival status. a The null hypothesis that cefiderocol is inferior to meropenem (with respect to the 12.5 noninferiority margin) was rejected, 2-sided p =0.001. No hypothesis tests were performed with respect to ACM at day 28. Abbreviations: ACM, all-cause mortality; APACHE, Acute Physiology and Chronic Health Evaluation; CI, confidence interval; mITT, modified intention-to-treat; n, number of subjects who died by the indicated timepoint The next table provides a sensitivity analysis for the “per pathogen” table presented in the discussion of important review issue #2 in Section 6.4.2. It examines ACM using the approach of considering subjects with unknown survival status as deaths rather than excluding them. The results are unchanged for most pathogens, given the paucity of unknown survival status, and overall remain consistent with the NI of cefiderocol to meropenem.

Table 59. All-Cause Mortality by Baseline Pathogens With Known Meropenem Susceptibility in mITT Population, Treating Unknown Survival Status as Death, APEKS-NP Trial Day 14 All-Cause Mortality Day 28 All-Cause Mortality Baseline Group or Pathogen Fetroja Meropenem Fetroja Meropenem Klebsiella pneumoniae 4/38 (10.5) 4/36 (11.1) 8/38 (21.1) 9/36 (25.0) Pseudomonas aeruginosa 2/20 (10.0) 4/17 (23.5) 2/20 (10.0) 5/17 (29.4) Acinetobacter baumannii complex 1/8 (12.5) 0/9 (0.0) 3/8 (37.5) 0/9 (0.0) Escherichia coli 3/18 (16.7) 3/21/ (14.3) 5/18 (27.8) 4/21 (19.0) Enterobacter cloacae complex 1/9 (11.1) 2/10 (20.0) 2/9 (22.2) 3/10 (30.0) Serratia marcescens 1/8 (12.5) 0/4 (0.0) 2/8 (25.0) 0/4 (0.0) Proteus mirabilis 0/2 (0.0) 1/5 (20.0) 0/2 (0.0) 1/5 (20.0) Source: adsl.xpt, adms.xpt. All values are expressed as n/N’ (%). The cefiderocol arm included 145 subjects; the meropenem arm included 147 subjects. For ACM at day 14, 0 cefiderocol subjects and 1 meropenem subject had unknown survival status; for ACM at day 28, 2 cefiderocol subjects and 1 meropenem subject had unknown survival status. The label reported results for “Other Enterobacterales,” which combines Enterobacter cloacae complex and Serratia marcescens. The results for ACM at Day 14 are Fetroja 2/16 (12.5), Meropenem 2/14 (14.3); the results for ACM at Day 28 are Fetroja 4/16 (25.0), Meropenem 3/14 (21.4). Abbreviations: ACM, all-cause mortality; mITT, modified intention-to-treat; n, number of subjects who died by the indicated timepoint; N’, number of subjects with the pathogen at baseline known to be meropenem suscept ble The following figure provides estimated per-arm probabilities of survival over time, between initial receipt of study medication and EOS (EOT +28 days (+/-3 days)). The cefiderocol arm’s estimated survival curve closely tracks but is slightly inferior to the meropenem arm’s curve almost through day 40, after which limited data points lead to vague estimates of survival probability.

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Figure 8. Kaplan-Meier Survival Curves in the mITT Population, APEKS-NP Trial

Source: adsl.xpt. Abbreviations: mITT, modified intention-to-treat Additional Analyses for Clinical Outcome The following table presents clinical outcome cure rates at different time points. The cefiderocol cure rates are uniformly smaller than, but close to, the meropenem rates. All of the CIs for the difference in cure rates include zero, indicating that the data do not provide suggestive evidence of between-arm differences in rates.

Table 60. Clinical Outcome at Different Time Points in the mITT Population, APEKS-NP Trial Time Point Cefiderocol Meropenem Difference % (CI) EA 120/145 (82.8) 122/147 (83.0) -0.3 (-8.8, 8.2) EOT 112/145 (77.2) 119/147 (81.0) -3.8 (-12.9, 5.2) TOC 94/145 (64.8) 98/147 (66.7) -2.0 (-12.5, 8.5) Source: adsl.xpt; adclo.xpt. All values in the cefiderocol and meropenem columns are expressed as n/N’ (%). Estimates of difference in clinical cure rates and construction of confidence intervals derived from use of Cochran-Mantel-Haenszel (CMH) stratum-weighted estimator, where subjects with indeterminate clinical status are considered treatment failures. 95.04% (rather than 95%) confidence intervals are reported, due to adjustment in alpha level due to performance of multiple interim analyses. The cefiderocol arm included 145 subjects; the meropenem arm included 147 subjects. Abbreviations: CI, confidence interval; EA, early assessment occurring at day 3 or 4; EOT, end of treatment; TOC, test-of-cure assessment occurring 7 days (±2) after the end of treatment; mITT, modified intention-to-treat; n, number of subjects who were clinical cures; N’, number of subjects in the mITT population of treatment arm Additional Analyses for Microbiological Outcome The microbiological outcome eradication rates at different time points are reported in the table below. Recall that these endpoints are only defined for subjects who had gram-negative pathogens detected at baseline. The EA results suggest that the meropenem eradication rate may be superior to the cefiderocol rate at this time point. At EOT and TOC, however, the two arms have similar eradication rates and both CIs for eradication rate differences include zero.

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Reference ID: 4676324 NDA 209445 / S-002 Cefiderocol (Fetroja)

Table 61. Microbiological Outcome at Different Time Points in the mITT Population, APEKS-NP Trial Time Point Cefiderocol Meropenem Difference % (CI) EA 52/124 (41.9) 68/127 (53.5) -12.4 (-24.4, -0.4) EOT 79/124 (63.7) 85/127 (66.9) -3.8 (-15.5, 8.0) TOC 59/124 (47.6) 61/127 (48.0) -1.4 (-13.5, 10.8) Source: adsl.xpt; admbo.xpt. All values in the cefiderocol and meropenem columns are expressed as n/N’ (%). Estimates of difference in eradication rates and construction of confidence intervals derived from use of Cochran-Mantel-Haenszel (CMH) stratum-weighted estimator, where subjects with indeterminate microbiological status are considered treatment failures. 95.04% (rather than 95%) confidence intervals are reported, due to adjustment in alpha level due to performance of multiple interim analyses. The cefiderocol arm included 124 subjects with gram-negative pathogens detected at baseline; the meropenem arm included 127 such subjects. Abbreviations: CI, confidence interval; EA, early assessment occurring at day 3 or 4; EOT, end of treatment; TOC, test-of-cure assessment occurring 7 days (±2) after the end of treatment; mITT, modified intention-to-treat; n, number of subjects for whom all baseline gram-negative were eradicated clinical cures; N’, number of subjects in the mITT population of treatment arm Subgroup Analyses of All-Cause Mortality at Day 14 The following table (Table 62) presents the results of analyses of the primary endpoint for a variety of demographic and baseline health status subgroups. The reader is cautioned that these are exploratory analyses that generally have modest statistical power. Per the Applicant, CIs for the difference in death rates were only constructed when a subgroup contained at least 10 subjects per arm. All of the CIs include zero, meaning that they do not provide strong suggestions of between-arm differences in survival at day 14.

Table 62. All-Cause Mortality at Day 14 in mITT Subgroups, APEKS-NP Trial Baseline Variable Subgroup Cefiderocol Meropenem Difference % (CI) Demographic characteristics Gender Male 14/99 (14.1) 10/100 (10.0) 4.1 (-4.9, 13.2) Female 4/46 (8.7) 7/46 (15.2) -6.5 (-19.7, 6.7) Age group <65 years* 8/65 (12.3) 5/57 (8.8) 3.5 (-7.3, 14.4) 65≤to <75 years 3/40 (7.5) 8/45 (17.8) -10.3 (-24.1, 3.6) ≥75 years 7/40 (17.5) 4/44 (9.1) 8.4 (-6.1, 23.0) Race White 13/102 (12.7) 15/98 (15.3) -2.6 (-12.2, 7.1) Black or African American 0/0 0/1 (0.0) Asian 5/41 (12.2) 2/43 (4.7) 7.5 (-4.3, 19.4) Other 0/2 (0.0) 0/3 (0.0) 0.0 Region North America 1/6 (16.7) 0/6 (0.0) 16.7 Europe 12/99 (12.1) 15/97 (15.5) -3.3 (-13.0, 6.3) Asia-Pacific 5/40 (12.5) 2/43 (4.7) 7.8 (-4.2, 19.9) Hispanic/Latino? No 18/137 (13.1) 17/136 (12.5) 0.6 (-7.3, 8.6) Yes 0/4 (0.0) 0/3 (0.0) 0.0 Baseline health status Diagnosis HABP 6/59 (10.2) 9/60 (15.0) -4.8 (-16.7, 7.1) VABP 9/59 (15.3) 8/63 (12.7) 2.6 (-9.8, 14.9) HCABP 3/27 (11.1) 0/23 (0.0) 11.1 (-0.8, 23.0) APACHE II score ≤15 6/74 (8.1) 5/76 (6.6) 1.5 (-6.8, 9.9)

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Baseline Variable Subgroup Cefiderocol Meropenem Difference % (CI) 16-19 5/31 (16.1) 3/25 (12.0) 4.1 (-14.1, 22.3) ≥20 7/40 (17.5) 9/45 (20.0) -2.5 (-19.1, 14.1) CPIS <6 9/72 (12.5) 12/88 (13.6) -1.1 (-11.6, 9.4) 6-7 6/59 (10.2) 2/40 (5.0) 5.2 (-5.1, 15.4) 8-9 3/12 (25.0) 2/15 (13.3) 11.7 (-18.3, 41.7) >9 0/2 (0.0) 1/3 (33.3) -33.3 Bacteremia? No 13/132 (9.8) 14/131 (10.7) -0.8 (-8.2, 6.5) Yes 5/13 (38.5) 3/15 (20.0) 18.5 (-14.9, 51.8) Creatinine clearance >120 mL/min 3/22 (13.6) 2/25 (8.0) 5.6 (-12.2, 23.5) >80-120 mL/min 4/33 (12.1) 3/35 (8.6) 3.55 (-11.0, 18.1) >50-80 mL/min 3/43 (7.0) 2/35 (5.7) 1.262 (-9.6, 12.1) 30-50 mL/min 2/27 (7.4) 6/31 (19.4) -11.9 (-29.0, 5.1) <30 mL/min 6/20 (30.0) 4/20 (20.0) 10.0 (-16.7, 36.7) MDRD-eGFR ≥90 4/35 (11.4) 5/46 (10.9) 0.6 (-13.3, 14.4) 60 to <90 7/48 (14.6) 3/38 (7.9) 6.7 (-6.5, 19.9) 30 to <60 2/42 (4.8) 4/41 (9.8) -5.0 (-16.1, 6.2) 15 to <30 3/9 (33.3) 3/10 (30.0) 3.3 <15 2/11 (18.2) 2/11 (18.2) 0.0 (-32.3, 32.3) Empiric treatment failure? No 12/97 (12.4) 11/99 (11.1) 1.3 (-7.8, 10.3) Yes 6/48 (12.5) 6/47 (12.8) -0.3 (-13.7, 13.1) Prior antibacterials? No 1/40 (2.5) 5/46 (10.9) -8.4 (-18.6, 1.9) Yes 17/105 (16.2) 12/100 (12.0) 4.2 (-5.3, 13.7) ICU admission? No 3/43 (7.0) 1/50 (2.0) 5.0 (-3.6, 13.5) Yes 15/102 (14.7) 16/96 (16.7) -2.0 (-12.1, 8.2) Ventilated? No 4/56 (7.1) 5/61 (8.2) -1.1 (-10.7, 8.6) Yes 14/89 (15.7) 12/85 (14.1) 1.6 (-9.0, 12.2) Meropenem nonsusceptible?a No 9/84 (10.7) 9/79 (11.4) -0.7 (-10.3, 9.0) Yes 6/35 (17.1) 6/30 (20.0) -2.9 (-21.9, 16.2) Meropenem MIC >8?b No 9/89 (10.1) 10/83 (12.0) -1.9 (-11.3, 7.5) Yes 6/30 (20.0) 5/26 (19.2) 0.8 (-20.1, 21.6) Top 5 gram-negative pathogens Klebsiella pneumoniae 5/48 (10.4) 5/44 (11.4) -0.9 (-13.7, 11.8) Pseudomonas aeruginosa 2/24 (8.3) 3/23 (13.0) -4.7 (-22.4, 13.0) Acinetobacter baumannii 5/23 (21.7) 4/24 (16.7) 5.1 (-17.5, 27.6) Escherichia coli 4/19 (21.1) 3/22 (13.6) 7.4 (-15.9, 30.7) Enterobacter cloacae 0/7 (0.0) 1/8 (12.5) -12.5 Source: adsl.xpt; admbo.xpt. All values in the cefiderocol and meropenem columns are expressed as n/N (%).

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Estimates of difference in mortality rates are equal to the difference in the cefiderocol and meropenem arms’ rates. Confidence intervals, using Wald method, are computed when both arms contain at least 10 subjects in the subgroup. Per Applicant, subjects with unknown survival status are not included in analyses. 95.04% (rather than 95%) confidence intervals are reported, per adjustment in alpha level due to performance of multiple interim analyses. The cefiderocol arm included 145 subjects; the meropenem arm included 147 subjects; one meropenem subject and zero cefiderocol subjects had unknown survival status at day 14. * The label reports age group mortality rates, treating unknown survival status as death. The only subject with unknown survival status was <65 years in the meropenem arm, so in the label that subgroup’s arm is reported as 6/58 (10.3). a Meropenem-nonsusceptibility based on CLSI. 63 subjects had unknown nonsusceptibility status and were not included in the subgroup analyses; these included the 41 members of the mITT population who did not have any gram-negative pathogens detected at baseline. b 63 subjects had unknown status and were not included in the subgroup analyses; these included the 41 members of the mITT population who did not have any gram-negative pathogens detected at baseline. Abbreviations: APACHE, Acute Physiology and Chronic Health Evaluation; CI, confidence interval; CLSI, Clinical and Laboratory Standards Institute; CPIS, clinical pulmonary infection score; eGFR, estimated glomerular filtration rate; HABP, hospital-acquired bacterial pneumonia; HCABP, healthcare-associated bacterial pneumonia; ICU, intensive care unit; MDRD, Modification of Diet in Renal Disease; MIC, minimum inhibitory concentration; mITT, modified intention-to-treat; n, number of subjects who died by day 14; N, number of subjects in subgroup with known survival status at day 14; VABP, ventilator-associated bacterial pneumonia 17. Clinical Safety Assessment Additional Information and Assessment

This section provides additional analysis on safety issues related to cefiderocol’s mechanism of action and other class effects of β-lactam drugs. There is also a complete listing of treatment- emergent AE (TEAE) by system organ class (SOC) without any grouped queries, an analysis of TEAEs and serious AEs (SAEs) by demographic subgroups, and subject-level listings of discontinuations and deaths. Time Trends for Iron Parameters Given cefiderocol’s siderophore-based mechanism of cell entry, iron parameters were measured. The values for hepcidin, total iron-binding capacity, iron, and transferrin saturation were analyzed over time from screening to TOC. Hepcidin is an acute phase reactant and normal values have not been established. The iron parameters trended in a linear fashion in both treatment groups and changes over time did not appear clinically significant. Hemoglobin and hematocrit declined more rapidly in the cefiderocol group as compared to the meropenem group by the EA and then remained low until the TOC. There was approximately a 1 g/dL decrease in hemoglobin and 2% decrease in hematocrit from baseline to TOC in the cefiderocol-treated patients. The hemoglobin and hematocrit appeared to be more stable in the meropenem group (b) (4) over time, but in both groups, these parameters improved by the FU visit.

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Figure 9. Observed Result for Hepcidin (nmol/L) Average Measurements Across Analysis Visit Actual Treatment for Period 01

32 Cefiderocol

31 Meropenem

Screening/Baseline Test of Cure (TOC)

Analysis Visit ordered by Analysis Visit (N) (ascending) Source: Reviewer Figure, created in JMP Clinical

Figure 10. Observed Result for Total Iron Binding Capacity (TIBC) (mcmol/L) Average Measurements Across Analysis Visit Actual Treatment for Period 01

40 Cefiderocol

Meropenem 39

Screening/Baseline Test of Cure (TOC)

Analysis Visit ordered by Analysis Visit (N) (ascending) Source: Reviewer Figure, created in JMP clinical

Figure 11. Observed Result for Iron (mcmol/L) Average Measurements Across Analysis Visit Actual Treatment for Period 01

8.5 Cefiderocol Meropenem

8.0

7.5

7.0

6.5

6.0

5.5

Screening/Baseline Test of Cure (TOC)

Analysis Visit ordered by Analysis Visit (N) (ascending) Source: Reviewer Figure, created in JMP clinical

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Figure 12. Observed Result for Transferrin Saturation (%) Average Measurements Across Analysis Visit Actual Treatment for Period 01 22.5 Cefiderocol 22.0 Meropenem 21.5

21.0

20.5

20.0

19.5

19.0

18.5

18.0

17.5

17.0 Screening/Baseline Test of Cure (TOC)

Analysis Visit ordered by Analysis Visit (N) (ascending) Source: Reviewer Figure, created in JMP Clinical

Figure 13. Observed Result for Hematocrit Average Measurements Across Analysis Visit Actual Treatment for Period 01

0.342 Cefiderocol

0.340 Meropenem

0.338

0.336

0.334

0.332

0.330

0.328

0.326

0.324

Analysis Visit ordered by Analysis Visit (N) (ascending) Source: Reviewer Figure, created in JMP Clinical

Figure 14. Observed Result for Hemoglobin (HGB) (g/L) Average Measurements Across Analysis Visit Actual Treatment for Period 01 112.5

112.0 Cefiderocol

111.5 Meropenem

111 0

110.5

110.0

109.5

109.0

108.5

108.0

107.5

107.0

106.5

106.0

Analysis Visit ordered by Analysis Vis t (N) (ascending) Source: Reviewer Figure, created in JMP Clinical

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Reference ID: 4676324 NDA 209445 / S-002 Cefiderocol (Fetroja) Hy’s Law Screening Four patients in the meropenem and two patients in the cefiderocol group met biochemical criteria of Hy’s law (AST or ALT ≥3x ULN, total BILI ≥2x ULN, and ALP <2x ULN), as shown in Figure 15. The two patients in the cefiderocol group are described further below. Neither patient had known chronic liver disease at the time of enrollment, but both had confounding medications and concurrent sepsis. Both had a fatal outcome. (b) (6) • Patient – 81-year-old female with aortic valve replacement, atrial flutter s/p ablation, CHF, chronic obstructive pulmonary disease, hypertension (HTN), and hypercholesterolemia who was admitted since day -9 for E. coli urinary tract infection (UTI) and septic shock. The APACHE II score was 48, and she was randomized to cefiderocol for VABP. On day 2, SAEs of hepatic enzyme increased and septic shock occurred. Despite vasopressors, she died on day 3 due to septic shock and lactic acidosis which was considered related to CHF due to septic shock. Concomitant medications included amiodarone, heparin, insulin, levothyroxine, methylprednisolone, omeprazole, and propofol. The liver enzymes are noted below:

•

(b) (6) Table 63. Liver Enzymes for Hy’s Law Screening for Patient AST ALT GGT Total BILI (RR =0-40 (RR =0-41 ALP (RR =35- (RR =6-71 (RR =0- ALB (RR =34- Day IU/L) IU/L) 130 IU/L) IU/L) 1.2 mg/dL) 48 g/L) 1 42 H 57 H 181 H 272 H 1.5 H 34 L 3 2544 H 2083 H 198 H 237 H 3.2 H 32 L Source: Applicant’s Narratives Abbreviations: ALB, albumin; ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BILI, bilirubin; GGT, gamma-glutamyl transferase; RR, reference range, H, high, L, low

(b) (6) • Patient – 57-year-old male with DM and CVA with recent acute MI and coronary artery bypass. On day -14, he had atrial fibrillation and chronic CHF and 3 days later, multiple organ dysfunction syndrome (MODS), acute kidney injury (AKI), cardiac arrest, and ischemic hepatitis. He was randomized to cefiderocol for VABP. On day 6, he had a mild rash that resolved on day 11. On day 9, cefiderocol was discontinued due to bacteremia and clinical ineffectiveness of antibacterial therapy for NP. SAEs of liver function test (LFT) increased and sepsis occurred. On day 10, he had hemodiafiltration due to anuria and worsened encephalopathy. On day 15, he developed liver failure and died due to MODS. Concomitant medications included amiodarone, levofloxacin, omeprazole, dalteparin, caspofungin, and acetaminophen. The liver enzymes are below. The ALP criteria of Hy’s Law was not met at the same time as the criteria for elevated AST/ALT and BILI.

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(b) (6) Table 64. Liver Enzymes for Hy’s Law Screening for Patient AST ALT ALP GGT Total BILI ALB PT-INR (RR =5-35 (RR =5-45 (RR =30- (RR =7-55 (RR =5-21 (RR =35- (RR =0.85 Day U/L) U/L) 120 U/L) U/L) mcmol/L) 52 g/L) -1.25) 1 23 H 116 H 238 H 316 H 22 H 26 L 2.22 H 3 31.9 H 64.5 H 45 H 188.4 H 16.6 H 24 L 1.28 H 9 184 H 179 H 291 H 104 H 12 H 27 L 1.76 H 15 382 H 628 H 647 H 185 H 47 H 29 L 2.18 H Source: Applicant’s Narratives Abbreviations: ALB, albumin; ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BILI, bilirubin; GGT, gamma-glutamyl transferase; PT-INR, prothrombin time-international normalized ratio; RR, reference range, H, high, L, low

Figure 15. Hy’s Law Plot Peak Liver Test Results Possible Hy's Law Case/Actual Treatment for Period 01 7

Yes 6 No 5 Cefiderocol

Meropenem 4

0 9

0 8

0 7

0 6

0 5

0 4

0 3

0 2

0 2 0 3 0 4 0 5 0 6 0 8 2 3 4 5 6 7 8 20 30 40 50 60 70 80 1 10

Peak ALT/ULN Source: Reviewer Figure, created in JMP Clinical Abbreviations: ALT, alanine aminotransferase; BILI, bilirubin; ULN, upper limit of normal Although both patients had several comorbidities and concomitant medications, a possible increase in liver enzymes from cefiderocol is not fully excluded. Increased liver tests is a labeled AR. The patients in the meropenem group are not discussed as increased liver tests are labeled ARs for meropenem as well. Renal Abnormalities The frequency of any postbaseline worse stage of renal function by estimated glomerular filtration rate (eGFR) using the derived GFR was slightly higher in the cefiderocol group than in the meropenem group. Patients with normal GFR at baseline who developed stage 3 or higher postbaseline worst stage are described below. The first three cases listed had confounding medical history (DM, HTN, or renal failure) and medications. The fourth case may have been confounded by loss of volume from bleeding and concomitant medications. The last case was least confounded and may have had a positive dechallenge with cefiderocol, but a narrative was not available for detailed history and causality assessment could not be made. In all cases, eGFR was calculated in mL/min/1.73 m2.

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(b) (6) • – 82-year-old white male with a history of DM, HTN, and myasthenia gravis received cefiderocol until day 22 for VABP. The eGFR decreased gradually from 114 to 57 by day 36. TEAEs included edema, herpetic infection, diarrhea, and metabolic alkalosis. The patient also had a bladder operation (balloon placement) on day 13 (indication not provided). Confounding medications may have included acyclovir and furosemide. (b) (6) • – 77-year-old white male with a history of DM, renal failure, and sepsis received cefiderocol until day 6 for HABP. The eGFR decreased from 101 to 46 at day 15, but improved to 121 by day 22. TEAEs included hypernatremia from day 7 to day 22. Confounding medications included furosemide until day 11 and amikacin from day 15 to day 16. (b) (6) • – 63-year-old Asian female with a history of HTN and DM received cefiderocol until day 10 for a HCABP. The eGFR decreased from 93 to 59 at day 25 and increased to 67 by day 39. TEAEs included dyspnea, pyrexia, hemoptysis and hypokalemia. (b) (6) • –73-year-old Asian female with a history of a neck mass with tumor extension pulmonary tuberculosis, and hypokalemia received cefiderocol for VABP until day 15. The eGFR declined sharply from 139 to 21 at day 14. Other TEAEs were postprocedural hemorrhage after tracheostomy, hypokalemia, gastroenteritis, chest pain, abnormal urinalysis, urine output decreased, and acute myocardial infarction (MI) on day 15 which led to death. At baseline, the urine contained 3+ blood and glucose, and on day 14, there was 2+ protein. The blood eosinophil count remained within the range of normal. Confounding medications included furosemide given to increase urine output. (b) (6) • – 53-year-old white male with a history of amyotrophic lateral sclerosis and respiratory failure received cefiderocol until day 8 for VABP. The eGFR decreased from 225 to 3 on day 8, and then improved to 155 on day 21. No TEAEs were reported.

Table 65. eGFR Shift Table, Safety Population Cefiderocol Meropenem Baseline GFR Category Postbaseline Worst Stage N=148 N=150 Total Subjects Any Worse Stage 40 (27.0) 37 (24.7) Stage 1: eGFR ≥90: Stage 2: eGFR 60-89 5 (3.4) 11 (7.3) Normal or high GFR Stage 3a: eGFR 45-59 3 (2) 1 (0.7) Stage 4: eGFR 15-29 1 (0.7) 0 Stage 5: eGFR <15 1 (0.7) 0 Stage 2: eGFR 60-89: Stage 3a: eGFR 45-59 10 (6.8) 8 (5.3) Mild GFR Stage 3b: eGFR 30-44 1 (0.7) 2 (1.3) Stage 4: eGFR 15-29 1 (0.7) 2 (1.3) Stage 5: eGFR <15 1 (0.7) 0 Stage 3a: eGFR 45-59: Stage 3b: eGFR 30-44 5 (3.4) 4 (2.7) Moderate GFR Stage 4: eGFR 15-29 3 (2) 2 (1.3) Stage 3b: eGFR 30-44: Stage 4: eGFR 15-29 5 (3.4) 4 (2.7) Moderate GFR Stage 5: eGFR <15 2 (1.4) 2 (1.3) Stage 4: eGFR 15-29: Severe GFR Stage 5: eGFR <15 2 (1.4) 1 (0.7) Source: ad b.xpt; Software: R All values are expressed as n (%). Abbreviations: eGFR, estimated glomerular filtration rate

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Reference ID: 4676324 NDA 209445 / S-002 Cefiderocol (Fetroja) Adverse Events by System Organ Class and Preferred Term A complete list of TEAEs by SOC and preferred term (PT) ordered by risk difference relative to treatment with cefiderocol (without reviewer grouped queries or FDA Medical Dictionary for Regulatory Activities Queries) is noted in the table below (Table 66).

Table 66. TEAEs by SOC and PT System Organ Class Cefiderocol Meropenem Total Risk Difference Preferred Term N=148 N=150 N=298 (95% CI) Infections and infestations 60 (40.5) 53 (35.3) 113 (37.9) 5.2 (-5.8, 16.2) Urinary tract infection 23 (15.5) 16 (10.7) 39 (13.1) 4.8 (-2.8, 12.4) Pneumonia 11 (7.4) 8 (5.3) 19 (6.4) 2.1 (-3.4, 7.6) Septic shock 5 (3.4) 2 (1.3) 7 (2.3) 2.1 (-1.3, 5.5) Urinary tract infection fungal 4 (2.7) 2 (1.3) 6 (2.0) 1.4 (-1.8, 4.6) Genitourinary tract infection 2 (1.4) 0 2 (0.7) 1.4 (-0.5, 3.3) Oral candidiasis 2 (1.4) 0 2 (0.7) 1.4 (-0.5, 3.3) Urethritis 2 (1.4) 0 2 (0.7) 1.4 (-0.5, 3.3) Clostridium difficile infection 4 (2.7) 3 (2.0) 7 (2.3) 0.7 (-2.7, 4.1) Sepsis 4 (2.7) 3 (2.0) 7 (2.3) 0.7 (-2.7, 4.1) Ascariasis 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Bacteremia 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Bacterial sepsis 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Conjunctivitis 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Device related infection 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Ear infection 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Escherichia urinary tract infection 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Fungal sepsis 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Herpes zoster 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Lung infection 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Pyelonephritis 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Pyelonephritis chronic 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Respiratory tract infection 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Spinal cord infection 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Streptococcal bacteremia 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Tracheitis 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Sinusitis 2 (1.4) 2 (1.3) 4 (1.3) 0.1 (-2.5, 2.7) Bronchitis bacterial 1 (0.7) 1 (0.7) 2 (0.7) 0.0 (-1.9, 1.9) Gastroenteritis 1 (0.7) 1 (0.7) 2 (0.7) 0.0 (-1.9, 1.9) Influenza 1 (0.7) 1 (0.7) 2 (0.7) 0.0 (-1.9, 1.9) Pneumonia bacterial 1 (0.7) 1 (0.7) 2 (0.7) 0.0 (-1.9, 1.9) Postoperative wound infection 1 (0.7) 1 (0.7) 2 (0.7) 0.0 (-1.9, 1.9) Pulmonary tuberculosis 1 (0.7) 1 (0.7) 2 (0.7) 0.0 (-1.9, 1.9) Bronchitis 2 (1.4) 3 (2.0) 5 (1.7) -0.6 (-3.5, 2.3) Acinetobacter bacteremia 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Acinetobacter infection 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Bacteriuria 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Brain abscess 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Candida infection 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Chronic sinusitis 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Clostridium difficile colitis 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Cystitis 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Fungal infection 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Gallbladder empyema 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Gangrene 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Infectious disease carrier 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Infectious pleural effusion 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) 122 Integrated Review Template, version date 2019/10/16

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System Organ Class Cefiderocol Meropenem Total Risk Difference Preferred Term N=148 N=150 N=298 (95% CI) Joint tuberculosis 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Liver abscess 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Meningitis 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Meningitis bacterial 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Meningoencephalitis bacterial 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Otitis media 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Pneumonia necrotising 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Pseudomonas infection 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Septic encephalopathy 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Skin candida 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Streptococcal sepsis 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Systemic candida 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Urinary tract infection bacterial 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Wound infection 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Tracheobronchitis 2 (1.4) 4 (2.7) 6 (2.0) -1.3 (-4.5, 1.9) Lung abscess 0 2 (1.3) 2 (0.7) -1.3 (-3.1, 0.5) Gastrointestinal disorders 41 (27.7) 36 (24.0) 77 (25.8) 3.7 (-6.2, 13.6) Nausea 4 (2.7) 2 (1.3) 6 (2.0) 1.4 (-1.8, 4.6) Abdominal pain 2 (1.4) 0 2 (0.7) 1.4 (-0.5, 3.3) Constipation 7 (4.7) 6 (4.0) 13 (4.4) 0.7 (-3.9, 5.3) Gastrointestinal hemorrhage 2 (1.4) 1 (0.7) 3 (1.0) 0.7 (-1.6, 3.0) Ileus paralytic 2 (1.4) 1 (0.7) 3 (1.0) 0.7 (-1.6, 3.0) Abdominal pain upper 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Abdominal wall hematoma 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Chronic gastritis 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Duodenitis 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Gastric hemorrhage 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Gastritis 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Hemorrhoids thrombosed 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Hypoesthesia oral 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Intestinal infarction 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Intestinal ischemia 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Intra-abdominal fluid collection 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Peptic ulcer 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Retroperitoneal hematoma 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Diarrhea 13 (8.8) 13 (8.7) 26 (8.7) 0.1 (-6.3, 6.5) Flatulence 2 (1.4) 2 (1.3) 4 (1.3) 0.1 (-2.5, 2.7) Upper gastrointestinal hemorrhage 2 (1.4) 2 (1.3) 4 (1.3) 0.1 (-2.5, 2.7) Gastritis erosive 1 (0.7) 1 (0.7) 2 (0.7) 0.0 (-1.9, 1.9) Ascites 1 (0.7) 2 (1.3) 3 (1.0) -0.6 (-2.9, 1.7) Acute abdomen 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Duodenal ulcer 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Duodenal ulcer hemorrhage 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Dysphagia 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Gastroesophageal reflux disease 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Intestinal hemorrhage 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Mouth hemorrhage 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Pancreatitis acute 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Dyspepsia 0 2 (1.3) 2 (0.7) -1.3 (-3.1, 0.5) Hemorrhoids 0 2 (1.3) 2 (0.7) -1.3 (-3.1, 0.5) Vomiting 1 (0.7) 4 (2.7) 5 (1.7) -2.0 (-4.9, 0.9)

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Reference ID: 4676324 NDA 209445 / S-002 Cefiderocol (Fetroja)

System Organ Class Cefiderocol Meropenem Total Risk Difference Preferred Term N=148 N=150 N=298 (95% CI) Cardiac disorders 31 (20.9) 27 (18.0) 58 (19.5) 2.9 (-6.1, 11.9) Atrial fibrillation 7 (4.7) 4 (2.7) 11 (3.7) 2.0 (-2.3, 6.3) Left ventricular dysfunction 3 (2.0) 0 3 (1.0) 2.0 (-0.3, 4.3) Cardiac arrest 7 (4.7) 5 (3.3) 12 (4.0) 1.4 (-3.1, 5.9) Acute myocardial infarction 2 (1.4) 0 2 (0.7) 1.4 (-0.5, 3.3) Tricuspid valve incompetence 2 (1.4) 0 2 (0.7) 1.4 (-0.5, 3.3) Bradycardia 3 (2.0) 2 (1.3) 5 (1.7) 0.7 (-2.2, 3.6) Cardio-respiratory arrest 3 (2.0) 2 (1.3) 5 (1.7) 0.7 (-2.2, 3.6) Ventricular extrasystoles 2 (1.4) 1 (0.7) 3 (1.0) 0.7 (-1.6, 3.0) Angina unstable 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Cardiac valve disease 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Coronary artery disease 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Dilatation atrial 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Dilatation ventricular 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Extrasystoles 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Hypertensive heart disease 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Intracardiac thrombus 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Myocardial infarction 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Pericardial disease 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Pericardial effusion 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Right atrial dilatation 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Right ventricular dilatation 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Right ventricular failure 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Supraventricular tachycardia 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Tachycardia 2 (1.4) 2 (1.3) 4 (1.3) 0.1 (-2.5, 2.7) Arrhythmia 1 (0.7) 1 (0.7) 2 (0.7) 0.0 (-1.9, 1.9) Atrial flutter 1 (0.7) 1 (0.7) 2 (0.7) 0.0 (-1.9, 1.9) Cardiac failure congestive 1 (0.7) 1 (0.7) 2 (0.7) 0.0 (-1.9, 1.9) Cardiovascular insufficiency 1 (0.7) 1 (0.7) 2 (0.7) 0.0 (-1.9, 1.9) Sinus tachycardia 1 (0.7) 2 (1.3) 3 (1.0) -0.6 (-2.9, 1.7) Cardiogenic shock 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Cardiopulmonary failure 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Cardiovascular disorder 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Pericarditis 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Supraventricular extrasystoles 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Cardiac failure 2 (1.4) 4 (2.7) 6 (2.0) -1.3 (-4.5, 1.9) Cardiac failure acute 0 2 (1.3) 2 (0.7) -1.3 (-3.1, 0.5) Respiratory, thoracic and mediastinal disorders 37 (25.0) 34 (22.7) 71 (23.8) 2.3 (-7.4, 12.0) Acute respiratory failure 6 (4.1) 1 (0.7) 7 (2.3) 3.4 (-0.0, 6.8) Pleural effusion 10 (6.8) 6 (4.0) 16 (5.4) 2.8 (-2.3, 7.9) Pulmonary hypertension 3 (2.0) 0 3 (1.0) 2.0 (-0.3, 4.3) Pulmonary edema 3 (2.0) 1 (0.7) 4 (1.3) 1.3 (-1.3, 3.9) Pneumonia aspiration 3 (2.0) 2 (1.3) 5 (1.7) 0.7 (-2.2, 3.6) Asthma 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Bronchial secretion retention 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Bronchospasm 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Bullous lung disease 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Cough 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Dyspnea 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Hemoptysis 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Laryngeal edema 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Nasal dryness 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Pleurisy 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) 124 Integrated Review Template, version date 2019/10/16

Reference ID: 4676324 NDA 209445 / S-002 Cefiderocol (Fetroja)

System Organ Class Cefiderocol Meropenem Total Risk Difference Preferred Term N=148 N=150 N=298 (95% CI) Pneumothorax spontaneous 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Stridor 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Tracheal ulcer 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Pulmonary artery thrombosis 3 (2.0) 3 (2.0) 6 (2.0) 0.0 (-3.2, 3.2) Acute respiratory distress syndrome 1 (0.7) 1 (0.7) 2 (0.7) 0.0 (-1.9, 1.9) Atelectasis 1 (0.7) 1 (0.7) 2 (0.7) 0.0 (-1.9, 1.9) Pneumothorax 1 (0.7) 1 (0.7) 2 (0.7) 0.0 (-1.9, 1.9) Tachypnea 1 (0.7) 1 (0.7) 2 (0.7) 0.0 (-1.9, 1.9) Hydrothorax 5 (3.4) 6 (4.0) 11 (3.7) -0.6 (-4.9, 3.7) Pulmonary congestion 2 (1.4) 3 (2.0) 5 (1.7) -0.6 (-3.5, 2.3) Respiratory failure 2 (1.4) 3 (2.0) 5 (1.7) -0.6 (-3.5, 2.3) COPD 1 (0.7) 2 (1.3) 3 (1.0) -0.6 (-2.9, 1.7) Pulmonary embolism 1 (0.7) 2 (1.3) 3 (1.0) -0.6 (-2.9, 1.7) Acute pulmonary edema 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Bronchial hyperreactivity 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Bronchiectasis 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Bronchopleural fistula 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Emphysema 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Hypoxia 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Paranasal sinus hypersecretion 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Pleuritic pain 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Pneumomediastinum 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Respiratory acidosis 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Respiratory distress 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Epistaxis 0 2 (1.3) 2 (0.7) -1.3 (-3.1, 0.5) Investigations 32 (21.6) 29 (19.3) 61 (20.5) 2.3 (-6.9, 11.5) Aspartate aminotransferase increased 10 (6.8) 6 (4.0) 16 (5.4) 2.8 (-2.3, 7.9) Alanine aminotransferase increased 9 (6.1) 6 (4.0) 15 (5.0) 2.1 (-2.9, 7.1) GGT increased 5 (3.4) 2 (1.3) 7 (2.3) 2.1 (-1.3, 5.5) Amylase increased 3 (2.0) 0 3 (1.0) 2.0 (-0.3, 4.3) Blood pressure increased 2 (1.4) 0 2 (0.7) 1.4 (-0.5, 3.3) Ejection fraction decreased 2 (1.4) 0 2 (0.7) 1.4 (-0.5, 3.3) Liver function test increased 2 (1.4) 0 2 (0.7) 1.4 (-0.5, 3.3) Blood creatinine increased 2 (1.4) 1 (0.7) 3 (1.0) 0.7 (-1.6, 3.0) Blood albumin decreased 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Hemoglobin decreased 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Protein total decreased 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Red blood cell count decreased 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Urine analysis abnormal 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Urine output decreased 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Transaminases increased 4 (2.7) 4 (2.7) 8 (2.7) 0.0 (-3.7, 3.7) Blood alkaline phosphatase increased 1 (0.7) 1 (0.7) 2 (0.7) 0.0 (-1.9, 1.9) Blood lactate dehydrogenase 1 (0.7) 1 (0.7) 2 (0.7) 0.0 (-1.9, 1.9) increased Liver function test abnormal 1 (0.7) 1 (0.7) 2 (0.7) 0.0 (-1.9, 1.9) Blood bilirubin increased 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Blood glucose increased 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Blood potassium decreased 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Blood potassium increased 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Blood urea increased 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Mean arterial pressure decreased 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) C-reactive protein increased 0 2 (1.3) 2 (0.7) -1.3 (-3.1, 0.5) Hepatic enzyme increased 4 (2.7) 10 (6.7) 14 (4.7) -4.0 (-8.8, 0.8)

125 Integrated Review Template, version date 2019/10/16

Reference ID: 4676324 NDA 209445 / S-002 Cefiderocol (Fetroja)

System Organ Class Cefiderocol Meropenem Total Risk Difference Preferred Term N=148 N=150 N=298 (95% CI) General disorders and administration site conditions 22 (14.9) 19 (12.7) 41 (13.8) 2.2 (-5.6, 10.0) Hyperthermia 2 (1.4) 1 (0.7) 3 (1.0) 0.7 (-1.6, 3.0) Asthenia 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Calcinosis 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Chest pain 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) General physical health deterioration 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Inflammation 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Malaise 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Mucosal atrophy 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Pain 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Sudden death 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Pyrexia 5 (3.4) 5 (3.3) 10 (3.4) 0.1 (-4.0, 4.2) Multiple organ dysfunction syndrome 4 (2.7) 4 (2.7) 8 (2.7) 0.0 (-3.7, 3.7) Chest discomfort 1 (0.7) 1 (0.7) 2 (0.7) 0.0 (-1.9, 1.9) Death 1 (0.7) 1 (0.7) 2 (0.7) 0.0 (-1.9, 1.9) Fatigue 1 (0.7) 1 (0.7) 2 (0.7) 0.0 (-1.9, 1.9) Edema peripheral 2 (1.4) 3 (2.0) 5 (1.7) -0.6 (-3.5, 2.3) Catheter site hemorrhage 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Granuloma 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Injection site edema 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Edema 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) SIRS 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Hypothermia 0 2 (1.3) 2 (0.7) -1.3 (-3.1, 0.5) Nervous system disorders 20 (13.5) 17 (11.3) 37 (12.4) 2.2 (-5.3, 9.7) Cerebrovascular accident 3 (2.0) 1 (0.7) 4 (1.3) 1.3 (-1.3, 3.9) Headache 3 (2.0) 1 (0.7) 4 (1.3) 1.3 (-1.3, 3.9) Intracranial pressure increased 2 (1.4) 1 (0.7) 3 (1.0) 0.7 (-1.6, 3.0) Cerebral calcification 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Cerebral ischemia 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Dizziness 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Hypoxic-ischemic encephalopathy 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Neuromyopathy 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Paresthesia 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Status epilepticus 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Stroke in evolution 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) White matter lesion 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Seizure 2 (1.4) 2 (1.3) 4 (1.3) 0.1 (-2.5, 2.7) Autonomic nervous system imbalance 1 (0.7) 1 (0.7) 2 (0.7) 0.0 (-1.9, 1.9) Encephalopathy 1 (0.7) 1 (0.7) 2 (0.7) 0.0 (-1.9, 1.9) Metabolic encephalopathy 1 (0.7) 1 (0.7) 2 (0.7) 0.0 (-1.9, 1.9) Brain injury 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Cerebral hematoma 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Coma 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) ICU-acquired weakness 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Lacunar stroke 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Paresis 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Brain edema 1 (0.7) 5 (3.3) 6 (2.0) -2.6 (-5.8, 0.6)

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Reference ID: 4676324 NDA 209445 / S-002 Cefiderocol (Fetroja)

System Organ Class Cefiderocol Meropenem Total Risk Difference Preferred Term N=148 N=150 N=298 (95% CI) Psychiatric disorders 17 (11.5) 14 (9.3) 31 (10.4) 2.2 (-4.7, 9.1) Anxiety 3 (2.0) 0 3 (1.0) 2.0 (-0.3, 4.3) Insomnia 5 (3.4) 3 (2.0) 8 (2.7) 1.4 (-2.3, 5.1) Delirium 5 (3.4) 4 (2.7) 9 (3.0) 0.7 (-3.2, 4.6) Depression 2 (1.4) 1 (0.7) 3 (1.0) 0.7 (-1.6, 3.0) Abnormal behaviour 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Hallucination, visual 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Persistent depressive disorder 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Restlessness 2 (1.4) 2 (1.3) 4 (1.3) 0.1 (-2.5, 2.7) Confusional state 1 (0.7) 1 (0.7) 2 (0.7) 0.0 (-1.9, 1.9) Depressed mood 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Disorientation 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Sleep disorder 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Agitation 1 (0.7) 3 (2.0) 4 (1.3) -1.3 (-3.9, 1.3) Injury, poisoning and procedural complications 6 (4.1) 3 (2.0) 9 (3.0) 2.1 (-1.8, 6.0) Post procedural hemorrhage 3 (2.0) 1 (0.7) 4 (1.3) 1.3 (-1.3, 3.9) Back injury 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Procedural pain 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Subarachnoid hemorrhage 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Laceration 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Splenic rupture 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Hepatobiliary disorders 8 (5.4) 6 (4.0) 14 (4.7) 1.4 (-3.4, 6.2) Cholestasis 2 (1.4) 0 2 (0.7) 1.4 (-0.5, 3.3) Cholecystitis 2 (1.4) 1 (0.7) 3 (1.0) 0.7 (-1.6, 3.0) Cholelithiasis 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Hepatic failure 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Hepatic vein dilatation 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Hepatomegaly 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Hypertransaminasemia 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Cholecystitis acute 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Hepatic cyst 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Hepatic function abnormal 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Hepatocellular injury 1 (0.7) 3 (2.0) 4 (1.3) -1.3 (-3.9, 1.3) Musculoskeletal and connective tissue disorder 5 (3.4) 4 (2.7) 9 (3.0) 0.7 (-3.2, 4.6) Gouty arthritis 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Muscle twitching 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Musculoskeletal stiffness 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Back pain 2 (1.4) 2 (1.3) 4 (1.3) 0.1 (-2.5, 2.7) Osteoarthritis 1 (0.7) 1 (0.7) 2 (0.7) 0.0 (-1.9, 1.9) Costochondritis 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Musculoskeletal pain 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Neoplasms benign, malignant and unspecified (incl cysts and polyps) 2 (1.4) 1 (0.7) 3 (1.0) 0.7 (-1.6, 3.0) Lung cancer metastatic 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Prostatic adenoma 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Adrenal adenoma 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Surgical and medical procedures 2 (1.4) 1 (0.7) 3 (1.0) 0.7 (-1.6, 3.0) Bladder operation 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Leg amputation 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Gastrostomy tube removal 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6)

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System Organ Class Cefiderocol Meropenem Total Risk Difference Preferred Term N=148 N=150 N=298 (95% CI) Endocrine disorders 1 (0.7) 1 (0.7) 2 (0.7) 0.0 (-1.9, 1.9) Hypothyroidism 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Adrenal insufficiency 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Blood and lymphatic system disorders 27 (18.2) 28 (18.7) 55 (18.5) -0.5 (-9.3, 8.3) Iron deficiency anemia 3 (2.0) 0 3 (1.0) 2.0 (-0.3, 4.3) Anemia of chronic disease 2 (1.4) 0 2 (0.7) 1.4 (-0.5, 3.3) Thrombocytosis 4 (2.7) 3 (2.0) 7 (2.3) 0.7 (-2.7, 4.1) Lymphadenopathy 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Normochromic normocytic anemia 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Anemia 12 (8.1) 12 (8.0) 24 (8.1) 0.1 (-6.1, 6.3) Leukocytosis 1 (0.7) 1 (0.7) 2 (0.7) 0.0 (-1.9, 1.9) Eosinophilia 1 (0.7) 2 (1.3) 3 (1.0) -0.6 (-2.9, 1.7) Disseminated intravascular coagulation 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Leukopenia 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Nephrogenic anemia 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Coagulopathy 1 (0.7) 3 (2.0) 4 (1.3) -1.3 (-3.9, 1.3) Hemorrhagic anemia 0 2 (1.3) 2 (0.7) -1.3 (-3.1, 0.5) Hypocoagulable state 0 2 (1.3) 2 (0.7) -1.3 (-3.1, 0.5) Thrombocytopenia 2 (1.4) 8 (5.3) 10 (3.4) -3.9 (-7.9, 0.1) Reproductive system and breast disorders 2 (1.4) 3 (2.0) 5 (1.7) -0.6 (-3.5, 2.3) Benign prostatic hyperplasia 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Prostatitis 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Scrotal swelling 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Scrotal ulcer 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Vulvovaginal pruritus 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Ear and labyrinth disorders 1 (0.7) 2 (1.3) 3 (1.0) -0.6 (-2.9, 1.7) Ear discomfort 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Hematotympanum 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Vestibular disorder 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Eye disorders 1 (0.7) 2 (1.3) 3 (1.0) -0.6 (-2.9, 1.7) Visual acuity reduced 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Amaurosis 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Cataract 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Macular degeneration 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Vision blurred 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Metabolism and nutrition disorders 43 (29.1) 47 (31.3) 90 (30.2) -2.2 (-12.6, 8.2) Hypomagnesemia 8 (5.4) 1 (0.7) 9 (3.0) 4.7 (0.8, 8.6) Hypoglycemia 6 (4.1) 3 (2.0) 9 (3.0) 2.1 (-1.8, 6.0) Hyperkalemia 4 (2.7) 1 (0.7) 5 (1.7) 2.0 (-0.9, 4.9) Hypocalcemia 4 (2.7) 1 (0.7) 5 (1.7) 2.0 (-0.9, 4.9) Hyperglycemia 4 (2.7) 2 (1.3) 6 (2.0) 1.4 (-1.8, 4.6) Hypochloremia 2 (1.4) 0 2 (0.7) 1.4 (-0.5, 3.3) Hyperuricemia 3 (2.0) 1 (0.7) 4 (1.3) 1.3 (-1.3, 3.9) Hypernatremia 2 (1.4) 1 (0.7) 3 (1.0) 0.7 (-1.6, 3.0) Diabetes mellitus 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Hypercholesterolemia 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Hyperinsulinemic hypoglycemia 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Iron deficiency 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Lactic acidosis 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Type 2 diabetes mellitus 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Hypophosphatemia 1 (0.7) 1 (0.7) 2 (0.7) 0.0 (-1.9, 1.9) Hypovolemia 1 (0.7) 1 (0.7) 2 (0.7) 0.0 (-1.9, 1.9) 128 Integrated Review Template, version date 2019/10/16

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System Organ Class Cefiderocol Meropenem Total Risk Difference Preferred Term N=148 N=150 N=298 (95% CI) Hypoproteinemia 3 (2.0) 4 (2.7) 7 (2.3) -0.7 (-4.1, 2.7) Acidosis 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Cerebral salt-wasting syndrome 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Hyperphosphatemia 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Metabolic syndrome 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Gout 1 (0.7) 3 (2.0) 4 (1.3) -1.3 (-3.9, 1.3) Metabolic alkalosis 1 (0.7) 3 (2.0) 4 (1.3) -1.3 (-3.9, 1.3) Hypoalbuminemia 5 (3.4) 8 (5.3) 13 (4.4) -1.9 (-6.5, 2.7) Electrolyte imbalance 0 4 (2.7) 4 (1.3) -2.7 (-5.3, -0.1) Hyponatremia 4 (2.7) 10 (6.7) 14 (4.7) -4.0 (-8.8, 0.8) Hypokalemia 16 (10.8) 23 (15.3) 39 (13.1) -4.5 (-12.1, 3.1) Renal and urinary disorders 8 (5.4) 13 (8.7) 21 (7.0) -3.3 (-9.1, 2.5) Anuria 2 (1.4) 1 (0.7) 3 (1.0) 0.7 (-1.6, 3.0) Hematuria 2 (1.4) 1 (0.7) 3 (1.0) 0.7 (-1.6, 3.0) Cystitis hemorrhagic 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Leukocyturia 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Renal failure 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Renal impairment 1 (0.7) 1 (0.7) 2 (0.7) 0.0 (-1.9, 1.9) Urinary retention 1 (0.7) 1 (0.7) 2 (0.7) 0.0 (-1.9, 1.9) Dysuria 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Hemorrhage urinary tract 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Neurogenic bladder 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Polyuria 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Renal hematoma 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Renal tubular acidosis 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Acute kidney injury 1 (0.7) 3 (2.0) 4 (1.3) -1.3 (-3.9, 1.3) Vascular disorders 18 (12.2) 28 (18.7) 46 (15.4) -6.5 (-14.7, 1.7) Aortic arteriosclerosis 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Aortic dilatation 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Deep vein thrombosis 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Essential hypertension 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Peripheral vascular disorder 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Post thrombotic syndrome 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Hypertensive crisis 1 (0.7) 1 (0.7) 2 (0.7) 0.0 (-1.9, 1.9) Vasospasm 1 (0.7) 1 (0.7) 2 (0.7) 0.0 (-1.9, 1.9) Venous thrombosis 1 (0.7) 1 (0.7) 2 (0.7) 0.0 (-1.9, 1.9) Phlebitis 3 (2.0) 4 (2.7) 7 (2.3) -0.7 (-4.1, 2.7) Angiosclerosis 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Brachiocephalic vein thrombosis 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Femoral artery embolism 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Hemodynamic instability 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Hot flush 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Hypovolemic shock 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Lymphostasis 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Shock hemorrhagic 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Hypertension 5 (3.4) 7 (4.7) 12 (4.0) -1.3 (-5.8, 3.2) Hypotension 2 (1.4) 10 (6.7) 12 (4.0) -5.3 (-9.7, -0.9) Skin and subcutaneous tissue disorders 11 (7.4) 23 (15.3) 34 (11.4) -7.9 (-15.0, -0.8) Skin lesion 2 (1.4) 0 2 (0.7) 1.4 (-0.5, 3.3) Dermatitis allergic 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Diabetic foot 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Palmar erythema 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Rash 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Rash erythematous 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) 129 Integrated Review Template, version date 2019/10/16

Reference ID: 4676324 NDA 209445 / S-002 Cefiderocol (Fetroja)

System Organ Class Cefiderocol Meropenem Total Risk Difference Preferred Term N=148 N=150 N=298 (95% CI) Skin irritation 1 (0.7) 0 1 (0.3) 0.7 (-0.6, 2.0) Dermatitis 1 (0.7) 1 (0.7) 2 (0.7) 0.0 (-1.9, 1.9) Dermatitis atopic 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Dermatitis diaper 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Drug eruption 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Eczema 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Intertrigo 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Papule 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Pruritus 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Rash macular 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Skin maceration 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Subcutaneous emphysema 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Urticaria 0 1 (0.7) 1 (0.3) -0.7 (-2.0, 0.6) Skin necrosis 0 2 (1.3) 2 (0.7) -1.3 (-3.1, 0.5) Decubitus ulcer 4 (2.7) 10 (6.7) 14 (4.7) -4.0 (-8.8, 0.8) Source: adae.xpt; Software: Python All values in the cefiderocol, meropenem, and total columns are expressed as n (%). Risk difference column shows absolute difference (with 95% confidence interval) between cefiderocol and meropenem. Treatment-emergent adverse events are defined as adverse events that started after the initial dose of study treatment or comparator and up to the EOS Abbreviations: CI, confidence interval; COPD, chronic obstructive pulmonary disease; EOS, end of study; GGT, gamma- glutamyltransferase; ICU, intensive care unit; N, number of subjects in treatment arm; n, number of subjects with adverse event; PT, preferred term; SIRS, systemic inflammatory response syndrome; SOC, system organ class Adverse Events Based on Demographic Subgroups The overall incidence of TEAEs in younger (<65 years or <75 years of age) patients was similar to those in older (≥65 years or ≥75 years of age) patients in the cefiderocol group, and similar across patients in the same age subgroups in the meropenem arm. However, patients ≥75 years of age had a higher number of SAEs than those <75 years of age in the cefiderocol group and patients ≥75 years of age in the meropenem arm. Asians had a TEAE frequency similar to those of whites in the cefiderocol group and patients in the meropenem group. The number of SAEs was higher than those of whites in the cefiderocol group and Asians in the meropenem subgroups. The possible reasons for this differences was discussed in Section 7.7.1 (Mortality by Subgroups).

Table 67. TEAE incidence by Baseline Characteristics, Safety Population Cefiderocol Meropenem N=148 N=150 Subgroup n (%) N n (%) N Any TEAE 130 (87.8) 148 129 (86) 150 Sex Female 39 (83) 47 40 (87) 46 Male 91 (90.1) 101 89 (85.6) 104 Age Group <65 years 57 (87.7) 65 49 (84.5) 58 ≥65 years 73 (88) 83 80 (87) 92 <75 years 95 (88) 108 88 (85.4) 103 ≥75 years 35 (87.5) 40 41 (87.2) 47

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Cefiderocol Meropenem N=148 N=150 Subgroup n (%) N n (%) N Race Asian 38 (86.4) 44 38 (86.4) 44 Black or African American 0 0 1 (100) 1 Other 2 (100) 2 4 (100) 4 White 90 (88.2) 102 85 (85) 100 Missing 0 0 1 (100) 1 Ethnicity Hispanic or Latino 3 (75) 4 3 (100) 3 Not Hispanic or Latino 123 (87.9) 140 118 (84.9) 139 Not reported 4 (100) 4 8 (100) 8 Region Asia-Pacific 37 (86) 43 38 (86.4) 44 Europe 87 (87.9) 99 85 (85) 100 North America 6 (100) 6 6 (100) 6 BMI group <30 kg/m2 101 (85.6) 118 94 (85.5) 110 ≥30 kg/m2 29 (96.7) 30 35 (87.5) 40 Creatine clearance group >80 (normal) 51 (92.7) 55 49 (80.3) 61 >50-80 (mild) 34 (77.3) 44 32 (86.5) 37 30-50 (moderate) 26 (89.7) 29 30 (93.8) 32 <30 (severe) 19 (95) 20 18 (90) 20 Source: adae.xpt; Software: R Abbreviations: BMI, body mass index; TEAE, treatment-emergent adverse event

Table 68. SAE Incidence by Baseline Characteristics, Safety Population Cefiderocol Meropenem N=148 N=150 Subgroup n (%) N n (%) N Any SAE 54 (36.5) 148 46 (30.7) 150 Sex Female 16 (34) 47 16 (34.8) 46 Male 38 (37.6) 101 30 (28.8) 104 Age group <65 years 26 (40) 65 18 (31) 58 ≥65 years 28 (33.7) 83 28 (30.4) 92 <75 years 36 (33.3) 108 34 (33) 103 ≥75 years 18 (45) 40 12 (25.5) 47 Race Asian 18 (40.9) 44 11 (25) 44 White 36 (35.3) 102 35 (35) 100 Ethnicity Hispanic or Latino 1 (25) 4 0 3 Not Hispanic or Latino 51 (36.4) 140 46 (33.1) 139 Not reported 2 (50) 4 0 8 Region Asia-Pacific 18 (41.9) 43 11 (25) 44 Europe 35 (35.4) 99 33 (33) 100 North America 1 (16.7) 6 2 (33.3) 6 BMI group <30 kg/m2 44 (37.3) 118 35 (31.8) 110 ≥30 kg/m2 10 (33.3) 30 11 (27.5) 40

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Cefiderocol Meropenem N=148 N=150 Subgroup n (%) N n (%) N Creatine clearance group >80 (normal) 22 (40) 55 16 (26.2) 61 >50-80 (mild) 13 (29.5) 44 7 (18.9) 37 30-50 (moderate) 9 (31) 29 14 (43.8) 32 <30 (severe) 10 (50) 20 9 (45) 20 Source: adae.xpt; Software: R Abbreviations: BMI, body mass index; SAE, serious adverse event

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Table 69. List of Treatment-Emergent Adverse Events Leading to Discontinuation, Safety Population, APEKS-NP Trial If Related, Study Confounders Day of Assessment of for TEAE; If NR, TEAE Duration (Days) Relatedness other cause of Subject ID Age, Sex PT VT SAE1 Onset TEAE Ex Invest. Rev. TEAE Cefiderocol (b) (6) 64, M Blood ALP Persistent elevated N 3 4 NR R Cholecystitis, increased (≥10x ALP linezolid, sepsis ULN) 63, M Brain edema Cerebral edema Y 8 1 8 NR NR Hemorrhagic CVA 61, M Stroke in evolution Worsening of Y 3 2 4 NR NR Extension of first ischemic stroke CVA prior to enrollment LFT increased (AST Elevation of liver Y 4 4 NR R Sepsis, ≥4x ULN) markers Amiodarone 78, M ALT increased (≥5x ALT increasing N 5 15 5 R R MOF, cipro, ULN) metamizole, propofol 67, F Gastric hemorrhage Acute gastric Y 2 1 2 NR NR Gastro- hemorrhage duodenitis, Crohn’s disease, heparin 83, M Septic shock Septic shock Y 2 2 3 NR NR Drug DC due to Lactic acidosis Lactic acidemia Y 3 1 3 NR death on Day 3, Intestinal infarction Mesenteric Y 3 1 3 NR not one infarction particular TEAE. Hepatocellular Hepatic cytolysis Y 3 1 3 NR Multiple causes injury (AST/ALT of death ≥20x ULN) 86, M LFT abnormal (AST Abnormal LFTs N 4 5 4 NR R Atorvastatin, ≥5x ULN) pantoprazole, nadroparin, furosemide

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If Related, Study Confounders Day of Assessment of for TEAE; If NR, TEAE Duration (Days) Relatedness other cause of 1 Subject ID(b) (6)Age, Sex PT VT SAE Onset TEAE Ex Invest. Rev. TEAE 77, M ALT increased Elevation of ALT Y 5 8 5 R R Hx of hepato- (≥10x ULN) megaly, Hepatic failure Unspecified hepatic N 5 8 5 R Ceftriaxone, failure enoxaparin, AST increased Elevation of AST till Y 5 6 5 R levofloxacin, 1161 u/l >19 upper propofol. limit 72, F Autonomic NS Dysautonomia Y 2 3 4 NR NR Cerebrovascular imbalance bleeding due to ruptured carotid artery aneurysm 73, F Acute MI Acute MI Y 15 2 15 NR R No cardiac hx. Chest pain TEAE on days 5-14, treated with tramadol. Abn ECG day 14 64, M ARDS ARDS Y 2 3 4 NR R ARDS likely 2o NP progression 84, M CVA Stroke Y 4 1 4 NR R Long-standing AF on bisoprolol, dalteparin, advanced age Meropenem (b) (6) 68, M Sepsis Worsening of sepsis Y 5 2 5 NR NR Sepsis may have been due to new infection 46, M Meningitis bacterial 2o postoperative N 5 6 NR NR Secondary bacterial meningitis meningitis from multiple brain surgeries 38, F Hepatic enzyme Liver event Y 5 5 R R Metoclopramide increased (AST (elevation of ALT, ≥4x, TB ≥2x ULN) AST, bilirubin

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If Related, Study Confounders Day of Assessment of for TEAE; If NR, TEAE Duration (Days) Relatedness other cause of Subject ID Age, Sex PT VT SAE1 Onset TEAE Ex Invest. Rev. TEAE (b) (6) 69, M Hepatic enzyme Elevation of liver Y 4 5 4 NR R Hy’s Law met on increased (AST/ALT enzymes >5x ULN Day 8. Low ≥50x TB ≥3x ULN) cardiac output (per hepatologist, less likely to be drug-related) 92, M DIC DIC Y 6 4 6 R R Inv strongly MODS MOF Y 6 4 6 R believed due to linezolid. No other cause noted. 70, M Hepatic enzyme Progression of liver N 3 3 NR NR Ongoing liver increased (AST enzymes elevation steatosis prior to ≥15x, ALT ≥9x Day 1; ULN) fluconazole, pantoprazole, paracetamol 75, F Hepatic enzyme Liver enzymes Y 8 8 NR R CHF, congestive increased (AST elevation hepatopathy ≥30x, ALT ≥10x, TB ≥2x ULN 67, M Hepatic enzyme Liver enzymes Y 3 3 NR NR Cardiac arrest, increased (AST/ALT elevation hypovolemic ≥50x, TB ≥2xULN) shock 1 day prior to increased liver enzymes, alcoholism 35, M Hepatic function Abnormal liver Y 5 32 5 NR R AST/ALT ≥1-1.5x abnormal (AST/ALT function ULN at baseline, ≥20x, TB ≥2x ULN) enoxaparin, paracetamol 67, M Brain edema Worsening of Y 3 1 3 NR NR SAH cerebral edema

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If Related, Study Confounders Day of Assessment of for TEAE; If NR, TEAE Duration (Days) Relatedness other cause of 1 Subject ID(b) (6) Age, Sex PT VT SAE Onset TEAE Ex Invest. Rev. TEAE 77, F SIRS SIRS Y 7 1 7 NR R Drug DC in Leukopenia Leukocytopenia N 7 7 NR response to treatment failure 82, F UTI UTI N 8 9 7 NR NR UGI hemorrhage UGI bleeding N 8 3 7 NR NR Pulmonary Pulmonary N 8 1 7 NR NR congestion congestion Acute respiratory Acute respiratory Y 8 9 7 NR R Drug DC in failure failure 2o to new response to onset HABP treatment failure 77, F Respiratory failure Progression of Y 3 1 3 NR R Drug DC due to respiratory failure treatment failure due to pneumonia 59, M Acinetobacter Acinetobacter N 11 11 NR NR New infection infection baumannii developed, pulmonary infection associated with lung cancer and bronchopleural fistula Source: adae.xpt; Software: Python, Patient narratives 1 Serious adverse events classified by Applicant in [dataset] Abbreviations: 2°, secondary; AF, atrial fibrillation; ALP, alkaline phosphatase; ALT, alanine aminotransferase; ARDS, acute respiratory distress syndrome; AST, aspartate aminotransferase; CVA, cerebrovascular accident; DC, discontinuation; DIC, disseminated intravascular coagulation; ECG, electrocardiogram; Ex, exposure; ID, identification; HABP, hospital-acquired bacterial pneumonia; LFT, liver function test; MI, myocardial infarction; MODS, multiple organ dysfunction syndrome; MOF, multiorgan failure; NR, not related; NS, nervous system; PT, preferred term; R, related; SAE, serious adverse event; SAH, subarachnoid hemorrhage; SIRS, systemic inflammatory response syndrome; TB, total bilirubin; TEAE, treatment-emergent adverse event; ULN, upper limit of normal; UGI, upper gastrointestinal; UTI, urinary tract infection; VT, verbatim term

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Table 70. List of Deaths in Safety Population, APEKS-NP Trial Assessment of Study Day Duration (Days) Relatedness TEAE Subj ID Age, Sex Preferred Term VT Death Onset TEAE Tx Inv Rev MO Comment Cefiderocol (b) (6) 64, M Cardio- Cardiopulmonary 8 8 1 4 NR NR Unlikely to survive at respiratory arrest collapse due to MI enrollment, too many concurrent illness, palliative care day 5 46, M MODS Multisystem organ 34 34 1 22 NR NR Cure/micro eradication at failure TOC, autopsy: MOF, compartment sx 18, F General physical Worsening 21 21 1 15 NR NR Worsening of polytrauma health physical state due deterioration to main disease - polytrauma. 63, M Brain edema Cerebral edema 8 8 1 8 NR NR Autopsy: No pneumonia, Brain edema due to hemorrhagic CVA. Unknown significance of 4- fold MIC increase for A. baumannii in BAL culture on day 3. 61, M Stroke in Worsening of 4 3 2 4 NR I Difficult to determine if evolution ischemic stroke MOF was due to stroke, original or new infectious process, no autopsy 53, M Cardiovascular Acute 4 4 1 4 NR NR CVA day -15 may have insufficiency cardiovascular predisposed to LBBB insufficiency which caused acute cardiovascular insufficiency 82, M PA thrombosis Thromboembolia 35 34 2 15 NR NR Recent CVA, age, of the PA immobility 78, M PA thrombosis Thromboembolia 29 29 1 5 NR NR Recent CVA, age, of the PA immobility

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Assessment of Study Day Duration (Days) Relatedness TEAE

Subj ID (b) (6) Age, Sex Preferred Term VT Death Onset TEAE Tx Inv Rev MO Comment 67, F Gastric Acute gastric 2 2 1 2 NR NR Crohn’s, gastroduodenitis, hemorrhage hemorrhage necrotizing colitis s/p jejunal tube exteriorization, colon resection on day -10 87, F MODS MOF 34 27 8 13 NR I Difficult to determine if MOF was 2o ischemic stroke, CHF, original infection (had CF at TOC), super infections (UTI, A. baumannii in tracheal cx at day 13), given amikacin, tigecycline 57, M MODS Worsening of 15 15 1 9 NR R LOE: cefiderocol DC due MOF to LOE, CF, S. marcescens bacteremia (from original NP), given ertapenem on day 9. Anuria, liver failure, MODS, sepsis on day 15; Autopsy: cardiopulmonary, endogenous intoxication with CHF 66, M Blood pressure Increased blood 8 7 2 8 NR NR Baseline SBP 197, not on increased pressure medication. Subarachnoid ICP increased Increased ICP 8 7 2 8 NR hemorrhage due to PCA dissection on day -6 83, M Hepatocellular Hepatic cytolysis 3 3 1 3 NR NR MOF (CAD, CABG, renal injury failure, ECMO) started Intestinal Mesenteric 3 3 1 3 NR prior to enrollment. infarction infarction Autopsy: cardiac arrest, Lactic acidosis Lactic acidemia 3 3 1 3 NR mesenteric ischemia, Septic shock Septic shock 3 2 2 3 NR hepatic failure, ARDS, E. coli bacteremia (original pathogen).

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Assessment of Study Day Duration (Days) Relatedness TEAE Subj ID Age, Sex Preferred Term VT Death Onset TEAE Tx Inv Rev MO Comment (b) (6) 56, M Lung cancer Worsening 3 3 1 2 NR NR Metastatic lung cancer, metastatic metastatic lung palliative care on day 2 cancer 81, F Septic shock Refractory septic 3 2 2 3 NR NR Ongoing shock, UTI before shock with lactic randomization, APACHE II acidosis 48. Biochemical criteria met for Hy’s law on day 3, likely due to sepsis 77, M Pneumonia New episode of 32 26 7 6 NR R LOE: Recurrence of E. pneumonia aerogenes pneumonia Death due to Death probably 32 32 1 6 NR (with 4-fold MIC increase pneumonia related to new in tracheal aspirate 0.06 to pneumonia 0.25), new E. coli pneumonia, given meropenem. CF and micro persistence at TOC. 84, F Intestinal Intestinal 10 10 1 8 NR R AR: unexplained cyanosis ischemia ischemia and coldness of lower limbs, CT confirmed intestinal ischemia on day 10. No autopsy. 68, M Pneumonia Pneumonia 18 18 1 9 NR R LOE: Recurrence of K. pneumoniae NP, given imipenem. 4-fold MIC increase of K. pneumoniae in tracheal aspirate (0.25 to 1). 86, M Pneumonia Broncho- 21 17 5 4 NR I Received only 4 days of pneumonia cefiderocol due to increased LFTs, then meropenem given until day 9.

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Assessment of Study Day Duration (Days) Relatedness TEAE Subj ID Age, Sex Preferred Term VT Death Onset TEAE Tx Inv Rev MO Comment (b) (6) 59, M MODS Acute MOF 9 9 1 8 NR R AR: unexplained bradycardia, cardiac arrest, MI, confounded by DM, HTN, AKI. LOE: MOF due to original NP contributed to death 78, M Acute respiratory Acute respiratory 8 8 1 7 NR R AR: unexpected unstable failure failure angina, MI during MI MI 8 8 1 7 NR treatment; confounded by PVD Peripheral 8 8 1 7 NR CAD, CVA circulation disorders 79, M Cardiac arrest Cardiac arrest 14 14 1 14 NR NR Cardiac history, cause of death: pulmonary HTN, coagulopathy (2o enoxaparin per Inv, but possibly related to cefiderocol as coagulopathy continued after stopping heparin) 77, M Cardiac arrest Asystole 15 15 1 5 NR NR MI, TBI, intracerebral hemorrhages may have predisposed to cardiac arrest 56, M Cardiac arrest Cardiac arrest 25 25 1 15 NR R LOE: Bilateral pneumonia developed day 11, CF day 15, meropenem, piperacillin-tazobactam given 84, M Cardiac arrest Cardiac arrest, 21 21 1 8 NR NR HTN, CHF; CVA on Day - asystole 19 may have predisposed to cardiac arrest

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Assessment of Study Day Duration (Days) Relatedness TEAE Subj ID Age, Sex Preferred Term VT Death Onset TEAE Tx Inv Rev MO Comment (b) (6) 72, F Autonomic NS Dysautonomia 4 2 3 4 NR NR No autopsy. Death imbalance certificate: cerebrovascular disease, ruptured carotid artery aneurysm, HTN, HABP 52, F Cardiac failure Severe 2 2 1 2 NR NR RHD, CHF, CKD, HTN decompensated heart failure 2o to severe mitral stenosis 85, M Sepsis Severe sepsis 2o 38 34 5 11 R R LOE: Recurrence of to HABP original NP (P. aeruginosa) on day 25, rescue abx given for CF 42, M Pulmonary Pulmonary edema 25 24 2 8 NR NR CC by TOC, CHF edema predominant cause at Day 24, NP on day 25 (no pathogen available) 65, M Cardio- Cardiopulmonary 43 43 1 15 NR NR Too many confounders: respiratory arrest arrest pulmonary TB at day 26, Aspiration pneumonia, ARF on day 40 66, M PE PE 5 5 1 5 NR NR Immobility, CVA may have predisposed to PE 73, F Acute MI Acute MI 16 15 2 15 NR R AR: chest pain, hypokalemia on day 4 may have led to MI 79, M Septic shock Septic shock 8 8 1 8 NR R LOE: due to original NP, confounded by candidemia

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Assessment of Study Day Duration (Days) Relatedness TEAE Subj ID Age, Sex Preferred Term VT Death Onset TEAE Tx Inv Rev MO Comment (b) (6) 52, M Acute respiratory Acute respiratory 15 11 5 11 NR I Cause of respiratory failure failure failure 2o to unclear: CN NP at central cause 2o baseline, super infection to acute on top of with A. baumannii in subacute SAH tracheal aspirate on day 3, SAH Acute on top of 15 11 5 11 NR 6, 11, no rescue abx; subacute, worsening of SAH, seizure progressive SAH on day 11, palliative care on day 15 64, M ARDS ARDS 4 2 3 4 NR R LOE: CF at day 3, worsening of VABP on chest x-ray, ARDS likely consequence of original VABP 91, M Cardiac failure Heart failure with 16 16 1 16 NR R LOE: CF at day 14 (EOT), pulmonary edema A pitti and E. coli (tracheal Pneumonia Severe 16 16 1 16 NR aspirate). Baseline pneumonia pathogen: A. nosocomialis and E. coli. CRF: subject died due to infection at randomization by day 28 64, M Sepsis Sepsis 40 40 1 15 NR R LOE: CF at TOC, 7 days after EOT, respiratory failure due to P. aeruginosa (tracheal aspirate), abx given. CN at baseline, but P. aeruginosa noted at day 3. Also had MSSA bacteremia, fungal sepsis, C. difficile. Autopsy: septicemia with MOF

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Assessment of Study Day Duration (Days) Relatedness TEAE Subj ID Age, Sex Preferred Term VT Death Onset TEAE Tx Inv Rev MO Comment (b) (6) 64, M Sudden death Sudden death 23 23 1 14 NR I Day 14, ventricular extrasystoles, resolved same day; day 21, sudden death (unknown cause, no autopsy. Hx esophageal CA with liver mets 84, M CVA Stroke 4 4 1 4 NR R AR: sudden CVA on treatment, confounded by cerebral arteriosclerosis, atrial fibrillation Meropenem (b) (6) 53, F Pneumonia Necrotizing 36 18 19 9 NR R LOE: Left-sided necrotising pneumonia pneumonia persisted, CF at TOC, cefepime, piperacillin-tazobactam given. Confounded by necrotizing bowel, comfort care on day 35 63, M Cardiac failure Acute heart failure 17 17 1 17 NR NR SAH on day -7 may have acute due to acute MI predisposed to MI with Brain edema Cerebral edema 17 17 1 17 NR subsequent CHF. Cardiac 2o SAH after arrest noted in labeling. rupture of Autopsy: SAH caused by saccular tearing of saccular aneurysm of aneurysm and acute MI cerebral vessels. 62, M Cardiac failure Acute heart failure 4 4 1 4 NR NR Hemorrhagic CVA on day - acute due to acute MI 12 may have predisposed Brain edema Cerebral edema 4 4 1 4 NR to MI with subsequent due to recurrent CHF. Brain edema likely hemorrhagic caused by CVA. No stroke. autopsy.

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Assessment of Study Day Duration (Days) Relatedness TEAE Subj ID Age, Sex Preferred Term VT Death Onset TEAE Tx Inv Rev MO Comment (b) (6) 63, M Brain edema Cerebral edema 48 48 1 21 NR I Brain edema likely due to 2o hemorrhagic CVA. Clinical cure at TOC stroke, recurrent (Day 21). day 28, received intracerebral TMP/SMX, cefoperazone, hematoma in the piperacillin for A. left hemisphere. baumannii, S. maltophilia, P. aeruginosa tracheobronchitis and developed new A. baumannii bacteremia. Autopsy: original K. pneumoniae NP and new P. aeruginosa endobronchitis. 68, F Sepsis Worsening of 6 5 2 5 NR NR Suspected cause of death: sepsis A. baumannii bacteremia probably due to infected hip phlegmon, cellulitis on day 3 66, M Death due to Death by 26 26 1 17 NR I Found dead, unknown pneumonia unknown reason cause, no autopsy 46, M Cardiovascular Acute 17 17 1 6 NR NR TBI, SDH day -5 may have insufficiency cardiovascular predisposed to cardiac insufficiency event. Meropenem DC day 8 due to secondary bacterial meningitis. Day 17, sharp “heart pain” and acute CV failure. Unclear if patient had an MI 38, F Cardiopulmonary Increasing 10 10 1 5 NR NR Meropenem DC day 5 due failure cardiopulmonary to hepatotoxicity. Day 10, insufficiency cardiopulmonary failure occurred. Autopsy: cardiopulmonary failure

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Subj ID (b) (6) Age, Sex Preferred Term VT Death Onset TEAE Tx Inv Rev MO Comment 67, F Brain edema Cerebral edema 13 13 1 13 NR NR CVA on day 1 and secondary CVA on day 13 with brain edema causing asystole 83, F PA thrombosis Thromboembolia 32 32 1 14 NR R AR: Drug-induced of the PA pulmonary embolism (labeled), confounded by CVA 63, M PA thrombosis Thromboembolia 22 22 1 19 NR R AR: Drug-induced of the PA pulmonary embolism (labeled), confounded by CVA 83, F MODS MOF 38 36 3 18 NR R LOE: MODS associated with relapse of NP and empyema (day 36, culture NA, but microbiological persistence P. mirabilis in day 18 tracheal aspirate, given cipro, doxycycline, meropenem 81, F Cardio- Cardiorespiratory 19 16 4 8 NR I Meropenem DC day 8 due respiratory arrest arrest to CF, cipro, piperacillin- tazobactam given. Day 19, had cardiorespiratory arrest due to dyspnea thought to have started after AVR on day -11, and refusal to remain on ventilator 69, F Cardio- Cardiorespiratory 7 7 1 7 NR NR Critical care myopathy respiratory arrest arrest since day -15, failed to wean off ventilator on day 4, died shortly after withdrawal of care day 7

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Assessment of Study Day Duration (Days) Relatedness TEAE Subj ID Age, Sex Preferred Term VT Death Onset TEAE Tx Inv Rev MO Comment (b) (6) 63, M Brain injury Severe brain 8 8 1 8 NR NR Intraparenchymal injury justifying hematoma with coma therapeutic since day -4, worsened on deescalation day 8. Died shortly after de-escalation in care on day 8. 69, M Hepatic enzyme Elevation of liver 8 4 5 4 NR R Biochemical criteria for increased enzymes >5x ULN Hy’s law met on day 8. Cardiogenic Cardiogenic 8 5 4 4 NR Meropenem DC on day 4 shock shock with MOF due to AST >10x ULN, ALT >5x ULN, given piperacillin-tazobactam. Confounders: low cardiac output (per hepatologist, less likely to be drug- related) 46, M Shock Severe 13 13 1 13 NR R LOE: 4-fold MIC increase, hemorrhagic hemorrhagic P. aeruginosa NP shock recurrence on day 11. Pseudomonas Pseudomonas 13 11 3 13 R Hemorrhagic shock infection resistant to considered to be related to meropenem low vitamin K 2o vancomycin (given for CNS endocarditis), meropenem 73, M Encephalopathy Worsening of 14 7 8 7 NR NR Encephalopathy since day multifactorial -7. Meropenem DC on day encephalopathy 7 as NP considered cured. Day 7, worsening encephalopathy due to sepsis from new infection (IAI due to previous cholecystectomy or line infection). Withdrawal of care on day 7 92, M MODS MOF 9 6 4 6 R R

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Assessment of Study Day Duration (Days) Relatedness TEAE Subj ID Age, Sex Preferred Term VT Death Onset TEAE Tx Inv Rev MO Comment DIC DIC 9 6 4 6 R AR: liver test elevation, decreased platelets (labeled ARs) (b) (6) 70, M Septic shock Septic shock 21 21 1 3 NR R LOE: Tx ended on day 3 Pneumonia Suspected 21 19 3 3 NR due to K. pneumoniae pneumonia persistence, but Cardiac failure Worsening 21 21 1 3 NR meropenem (nonstudy cardiac failure drug given until day 12). Pneumonia and septic shock on day 19, given rescue abx 75, F Cardiac failure Progression of 11 8 4 8 NR NR Meropenem DC due to cardiac failure increased LFTs on day 8. CHF on day 8. Died on day 11 due to CHF (hx of CHF, cardiomyopathy) 67, M Cardiovascular Progression of 4 2 3 3 NR NR Accidental fall with femoral disorder cardiovascular fracture on day -12, s/p instability endoprosthesis complicated by femoral artery embolism and splenic rupture, coagulopathy on day 2. Early death on day 4 due to CHF, hemorrhagic shock 67, M Brain edema Worsening of 3 3 1 3 NR NR SAH due to intracranial cerebral edema aneurysm and cerebral edema since day -4. Brain edema worsened on day 3. Died same day despite treatment with mannitol. No autopsy

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Assessment of Study Day Duration (Days) Relatedness TEAE Subj ID Age, Sex Preferred Term VT Death Onset TEAE Tx Inv Rev MO Comment (b) (6) 70, M Cardiac failure Worsening of 19 19 1 10 NR R LOE: K. oxytoca (one of congestive congestive heart the baseline NP failure pathogens) persisted, pneumonia on day 18, ciprofloxacin given, CHF may have been precipitated by NP. Confounded by hx of CHF, ischemic cardiomyopathy 69, F Hypotension Arterial 28 28 1 15 NR NR Cardiac arrest likely hypotension precipitated by CVA on caused by heart day -6 failure Cardiac arrest cardiac arrest 28 28 1 15 NR 80, M Cardiac failure Cardiovascular 17 17 1 15 NR NR Cardiac arrest and failure failure likely due to lacunar CVA Cardiac arrest Asystole 17 17 1 15 NR on day 13. Hx of CVA, AF, CHF 77, F Cardiac arrest Heart 7 7 1 7 NR I SIRS on day 7, colistin asystole/cardiac given. Appeared to be arrest infectious, but no source SIRS SIRS 7 7 1 7 NR identified. CF at EOT, possibly due to LOE. Also had hemorrhagic CVA on day -12 which may have predisposed to cardiac arrest 70, F Cardiac arrest Heart 20 20 1 5 NR R LOE: meropenem asystole/cardiac discontinued day 5 due to arrest CF/micro persistence, UTI Aggravation of 20 18 3 5 NR rescue abx given. UTI Pneumonia and UTI on Pneumonia VABP relapse 20 18 3 5 NR days 18 (S. maltophilia in tracheal cx). Cardiac arrest may have been precipitated by ICH. 148 Integrated Review Template, version date 2019/10/16

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Subj ID(b) (6) Age, Sex Preferred Term VT Death Onset TEAE Tx Inv Rev MO Comment 55, M ICP increased Elevated 16 14 3 8 NR NR Neuroendocrine lung intracerebral tumor with brain pressure metastases stage IV likely Respiratory Impending 16 14 3 8 NR contributed to respiratory failure respiratory failure failure with increased ICP 2o to elevated pressure. Clinical cure intracerebral noted at TOC pressure 2o to brain metastasis 49, F Hypovolemia Hypovolemia 22 21 2 7 NR NR Clinical cure and discharge Acute abdomen Acute abdomen 22 21 2 7 NR on day 20, readmitted at secondary to OSH for acute abdomen 2o ruptured tumor to ruptured tumor recently diagnosed 71, M MODS MOD 14 14 1 7 NR I DC home on day 12, had clinical cure at EOT. Found dead in bed by wife on day 14. Death reported as due to MODS given hx of DM, CKD, cardiac arrhythmia 72, M MODS MODS 26 26 1 15 NR R LOE: suspected pneumonia on day 24 (no pathogen), given rescue abx, MODs considered related to pneumonia and CHF 79, M Sepsis Sepsis 29 25 5 10 NR R LOE: Pneumonia with S. Respiratory Impending 29 24 6 10 NR marcescens on day 25, failure respiratory failure confounded by palliative care same day

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Assessment of Study Day Duration (Days) Relatedness TEAE Subj ID Age, Sex Preferred Term VT Death Onset TEAE Tx Inv Rev MO Comment (b) (6) 77, F Respiratory Progression of 3 3 1 3 NR R Inv reported treatment failure respiratory failure failure (LOE) and colistin due to pneumonia was started for NP. Respiratory failure was due to NP and patient withdrawn from study on day 3 59, M Bronchopleural Bronchial stump 14 13 2 11 NR NR Had slow response to fistula leak meropenem (persistent (insufficiency) fevers), but K. pneumoniae NP eradicated. Hx of lung cancer s/p left pulmonectomy on day -20. A. baumannii pneumonia on day 11, colistin given. Death due to bronchopleural fistula, leak repair unsuccessful. Source: adae.xpt; Software: Python, Patient narratives Abbreviations: 2°, secondary; ALP, alkaline phosphatase; ALT, alanine aminotransferase; AKI, acute kidney injury; APACHE, Acute Physiology and Chronic Health Evaluation; AR, adverse reaction; ARDS, acute respiratory distress syndrome; AST, aspartate aminotransferase; AVR, aortic valve replacement; BAL, bronchoalveolar lavage; CABG, coronary artery bypass grafting; CAD, coronary artery disease; CF, cardiac failure; CHF, congestive heart failure; CKD, chronic kidney disease; CN, culture negative; CNS, central nervous system; CT, computed tomography; CVA, cerebrovascular accident; DC, discontinuation; DIC, disseminated intravascular coagulation; DM, diabetes mellitus; ECMO, extracorporeal membrane oxygenation; EOT, end of treatment; Ex, exposure; Hx, history of; I, intermediate; HTN, hypertension; IAI, intra-abdominal infection; ICP, intracranial pressure; ICH, International Conference on Harmonisation; ID, identification; IV, intravenous; LBBB, left bundle branch block; LFT, liver function test; LOE, lack of efficacy; MI, myocardial infarction; MIC, minimum inhibitory concentration; MO, medical officer; MODS, multiple organ dysfunction syndrome; MOF, multiorgan failure; NP, nosocomial pneumonia; NR, not related; NS, nervous system; OSH, outside hospital; PA, pulmonary artery; PCA, posterior cerebral artery; PVD, peripheral vascular disease; R, related; RHD, rheumatic heart disease; SAE, serious adverse event; SAH, subarachnoid hemorrhage; SBP, systolic blood pressure; SDH, subdural hematoma; SIRS, systemic inflammatory response syndrome; TB, total bilirubin; TBI, traumatic brain injury; TEAE, treatment-emergent adverse event; TMP, trimethoprim; TOC, test of cure; Tx, treatment; UGI, upper gastrointestinal; ULN, upper limit of normal; UTI, urinary tract infection; VT, verbatim term; VABP, ventilator-associated bacterial pneumonia

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18. Mechanism of Action/Drug Resistance Additional Information and Assessment

The nonclinical microbiology assessments of the mechanism of action of cefiderocol and drug resistance to cefiderocol were previously described. See review for original NDA 209445 (Division of Anti-Infectives 2019). The new studies included in the sNDA are updated surveillance data and molecular characterization of surveillance isolates, in vivo activity against (b) (4) and under iron overload condition, and data on activity against efflux pumps. The key findings are below. In Vitro Activity The in vitro susceptibility testing of 38,288 clinical isolates collected during the period 2014 to 2018 from North America and European countries to cefiderocol was conducted using Iron Depleted Cation Adjusted Muller Hinton Broth (ID-CAMHB) in surveillance studies. The cefiderocol MIC required to inhibit 90% of tested isolates (MIC90) for Enterobacterales, P. aeruginosa, A. baumannii complex, B. cepacia complex, and S. maltophilia were 1, 0.5, 2, 0.25, and 0.5 mcg/mL, respectively (Table 71). The cefiderocol MIC90 values were 4, 2, and 1 mcg/mL against 814 meropenem-nonsusceptible (MEPM-NS, defined as meropenem MIC ≥2 mcg/mL for Enterobacterales and meropenem MIC ≥4 mcg/mL for P. aeruginosa and A. (b) (4) (b) (4) baumannii) Enterobacterales, MEPM-NS A. baumannii, and MEPM-NS P. aeruginosa, respectively (Table 72). The MIC90 values of cefiderocol for the multidrug-resistant (MDR, defined as nonsusceptible to the antimicrobial agent in three antimicrobial categories) and extensively drug-resistant (XDR, defined as nonsusceptible to the antimicrobial agent in four antimicrobial categories) subsets of Enterobacterales, A. baumannii, and P. aeruginosa were same as the MIC90s for MEPM-NS isolates.

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Table 71. In Vitro Activity of Cefiderocol Against Gram-Negative Pathogens MIC Range MIC50 MIC90 Pathogen (No. of Isolates) (mcg/mL) (mcg/mL) (mcg/mL) Achromobacter spp. (27)a <0.03-64 0.25 1 Acinetobacter baumannii complex (4185) ≤0.002->256 0.12 2 Burkholderia cepacia complex (265) ≤0.002-128 0.015 0.25 Burkholderia pseudomallei (271) <0.03-32 0.06 1 Citrobacter freundii complex (1138) ≤0.002-8 0.06 0.5 Citrobacter koseri (670) 0.004-8 0.25 0.5 Enterobacter cloacae complex (2580) ≤0.002-128 0.25 1 Escherichia coli (6424) ≤0.002-32 0.12 1 Klebsiella aerogenes (1175) ≤0.002-8 0.12 0.5 Klebsiella oxytoca (1780) ≤0.002-4 0.06 0.25 Klebsiella pneumoniae (5798) ≤0.002-128 0.12 1 Morganella morganii (801) ≤0.002->256 0.12 0.25 Proteus mirabilis (924) ≤0.002->256 0.015 0.12 Proteus vulgaris (552) ≤0.002-0.5 0.015 0.12 Providencia rettgeri (378) ≤0.002->256 0.015 0.12 Pseudomonas aeruginosa (6213) ≤0.002-8 0.12 0.5 Serratia marcescens (3092) ≤0.002-128 0.12 0.5 Stenotrophomonas maltophilia (1565) ≤0.002-128 0.06 0.5 Source: Study Report: S-649266-EB-387-N Table 2; Report S-649266-EF-304-N; Study Report: S-649266-EF-312-N; compassionate use Table 15 in Addendum -HABP/VABP a Achromobacter spp (n=11) from compassionate use patients Abbreviations: MIC, minimum inhibitory concentration

Table 72. In Vitro Activity of Cefiderocol Against Resistant Gram-Negative Pathogens MIC Range MIC50 MIC90 Pathogen (No. of Isolates) (mcg/mL) (mcg/mL) (mcg/mL) Enterobacterales (25995) ≤0.002->256 0.12 1 MEPM-S Enterobacterales (25181) a ≤0.002->256 NA 0.5 MEPM-NS Enterobacterales (814) b 0.004->256 1 4 MDR Enterobacterales (923)c 0.004->256 1 4 XDR Enterobacterales (204)d 0.008->256 1 4 Escherichia coli (6424) ≤0.002-32 0.12 1 MEPM-S E. coli (6391) a ≤0.002-8 NA 0.5 MEPM-NS E. coli (33) b 0.015-32 NA 4 Klebsiella pneumoniae (5798) ≤0.002-128 0.12 1 MEPM-S K. pneumoniae (5245) a ≤0.002-8 NA 1 MEPM-NS K. pneumoniae (553) b 0.008-128 NA 4 Klebsiella oxytoca (1780) ≤0.002-4 0.06 0.25 MEPM-S K. oxytoca (1764) a ≤0.002-4 NA 0.25 MEPM-NS K. oxytoca (16) b 0.03-4 NA 4 Enterobacter cloacae (2235) ≤0.002-128 0.25 1 MEPM-S E. cloacae (2163) a ≤0.002-128 NA 1 MEPM-NS E. cloacae (72) b 0.06-8 NA 4 Klebsiella aerogenes (1175) ≤0.002-8 0.12 0.5 MEPM-S K. aerogenes (1156) a ≤0.002-8 NA 0.5 MEPM-NS K. aerogenes (19) b 0.06-2 NA 1 Citrobacter freundii complex (1138) ≤0.002-8 0.06 0.5 MEPM-S C. freundii complex (1111) a ≤0.002-4 NA 0.5 MEPM-NS C. freundii complex (27) b 0.008-8 NA 2 Citrobacter koseri (668) 0.004-8 0.25 0.5 MEPM-S C. koseri (2) a 0.004-8 0.25 0.5 MEPM-NS C. koseri (2) b 0.25-4 NA -

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MIC Range MIC50 MIC90 Pathogen (No. of Isolates) (mcg/mL) (mcg/mL) (mcg/mL) Serratia marcescens (3092) ≤0.002-128 0.12 0.5 MEPM-S S. marcescens (3023) a ≤0.002-32 NA 0.25 MEPM-NS S. marcescens (69) b 0.008-128 NA 2 Nonfermenters Pseudomonas aeruginosa (6213) ≤0.002-8 0.12 0.5 MEPM-S P. aeruginosa (4797) a ≤0.002-8 0.5 MEPM-NS P. aeruginosa (1416) b ≤0.002-8 0.25 1 MDR P. aeruginosa (638)c ≤0.002-8 0.25 1 XDR P. aeruginosa (12)d 0.03-2 0.25 1 Acinetobacter baumannii (3583) ≤0.002->256 0.12 2 MEPM-S A. baumannii (1323) a 0.004->256 NA 0.5 MEPM-NS A. baumannii (2260) b ≤0.002->256 0.25 2 MDR A. baumannii (2154)c ≤0.002->256 0.25 2 XDR A. baumannii (302)d 0.03-64 0.25 2 Source: S-649266-EB-387-N, Table 2 and Response to FDA Information Request dated 29 May 2020 (eCTD 0067). Nonsusceptible was defined using the following criteria: For Enterobacterales: Meropenem MIC: ≥2 mcg/mL, Cefepime MIC: ≥4 mcg/mL, Ciprofloxacin MIC: ≥0.5 mcg/mL, Colistin MIC: ≥4 mcg/mL. For P. aeruginosa: Meropenem MIC: ≥4 mcg/mL, Cefepime MIC: ≥16 mcg/mL, Ciprofloxacin MIC: ≥1 mcg/mL, Colistin MIC: ≥4 mcg/mL. For A. baumannii: Meropenem MIC: ≥4 mcg/mL, Cefepime MIC: ≥16 mcg/mL, Ciprofloxacin MIC: ≥2 mcg/mL, Colistin MIC: ≥4 mcg/mL. a MEPM-S strain was defined as the strains which show susceptible to MEPM. For Enterobacterales MEPM MIC: ≤1 mcg/mL. For P. aeruginosa and Acinetobacter spp. MEPM MIC: ≤2 mcg/mL b MEPM-NS strain was defined as the strains which show nonsusceptible to MEPM. c MDR strains was defined as the strains which shows nonsusceptible to the antimicrobial agent in 3 antimicrobial categories. d XDR strains was defined as the strains which shows nonsusceptible to the antimicrobial agent in 4 antimicrobial categories. Abbreviations: MIC, minimum inhibitory concentration; NA, not available The percent susceptibility of surveillance isolates to cefiderocol was examined for isolates nonsusceptible to cefepime, ceftazidime-avibactam and ceftolozane-tazobactam in the SIDERO- WT study (Table 73). Cefiderocol is active in vitro against Enterobacterales and P. aeruginosa that are resistant to cefepime, ceftazidime-avibactam and ceftolozane-tazobactam. However, this activity would depend on the resistance mechanisms and β-lactamases present in the bacteria.

Table 73. Percentage (%) of Cefiderocol Susceptible Isolates Against Cefepime-, Ceftazidime- Avibactam-, and Ceftolozane/Tazobactam-Nonsusceptible Isolates From SIDERO-WT

Source: Table 23 section 2.7.2.4 addendum-HABP/VABP of the Application Abbreviations: MIC, minimum inhibitory concentration

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Reference ID: 4676324 NDA 209445 / S-002 Cefiderocol (Fetroja) Of the studies providing external validations, cefiderocol MIC range of 0.03 to 4 mcg/mL were noted for 66 S. maltophilia isolates in the surveillance study from Canada (study S-649266-EF- 311-N) although MIC90 values were similar to that observed in surveillance studies conducted in the United States and Europe. Additionally, cefiderocol MIC90 values for carbapenem-resistant isolates of Enterobacterales (n=305), P. aeruginosa (n=111) and A. baumannii (n=99) obtained from the Public Health England’s Antimicrobial Resistance and Healthcare Associated Infections Reference Unit were 4, 8 and 16 mcg/mL, respectively (S-649266-EF-329-N). Cefiderocol is active in vitro against A. baumannii complex, B. cepacia complex, Citrobacter freundii complex, Citrobacter koseri, E. coli, E. cloacae complex, Klebsiella aerogenes, Klebsiella oxytoca, K. pneumoniae, Morganella morganii, Proteus mirabilis, Proteus vulgaris, Providencia rettgeri, P. aeruginosa, Serratia marcescens, and Stenotrophomonas maltophilia. However, the MIC90 values maybe impacted by specific geographical locations. The cefiderocol MIC90 values against meropenem nonsusceptible Enterobacterales and A. baumannii isolates were four- or eight-fold fold higher compared to the MIC90 values for meropenem-susceptible isolates in the surveillance studies. Cross-resistance between cefiderocol and β-lactam is observed for isolates that are resistant to β-lactam and β-lactam/β-lactamase inhibitors based on the mechanism of action and mechanism of resistance. Burkholderia. pseudomallei B. pseudomallei is the causative agent of melioidosis, which is characterized by a variety of symptoms ranging from self-limiting abscess to sepsis and dissemination to the solid organs and brain. Melioidosis is endemic in Thailand and northern Australia and other tropical regions. The cefiderocol MIC90 against 271 B. pseudomallei isolates from Australia was 1 mcg/mL (cefiderocol MIC range ≤0.03 to 32 mcg/mL) (S-649266-EF-312-N). Although infections with B. pseudomallei has been documented in military personnel from the United States and can result in environmentally acquired respiratory tract illness, the pathogen is not associated with HABP/VABP. Additionally, B. pseudomallei is classified by the Centers for Disease Control and Prevention as a category B bioterrorism agent and the activity of cefiderocol (b) (4) against B. pseudomallei will need to be ascertained in clinical trials.

Achromobacter spp. Achromobacter species are commonly found in the environment and may colonize the human gastrointestinal (GI) tract. They are opportunistic pathogens and can cause respiratory tract infections and bacteremia in immunocompromised patients such as cancer patients, lung transplant patients, patients with cystic fibrosis, and patients with chronic renal failure. The cefiderocol MIC90 against 16 isolates of Achromobacter spp. was 1 mcg/mL (cefiderocol MIC range <0.03–16 mcg/mL). Data for 11 isolates from patient receiving compassionate use of cefiderocol was provided. Inclusion of these data results in a cefiderocol MIC range of <0.03 to 64 mcg/mL but does not impact the cefiderocol MIC90 values. Based on data against Achromobacter species, it can be included in the second list of pathogens in the microbiology section of the labeling.

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Reference ID: 4676324 NDA 209445 / S-002 Cefiderocol (Fetroja) Resistance The new information on the molecular characterization of gram-negative clinical isolates collected in the SIDERO-WT-2015 and -2016 studies is described in this section. To understand the potential mechanisms of resistance and activity against resistant bacteria, the presence of β- lactamase and carbapenemase in meropenem nonsusceptible isolates (meropenem MIC: ≥2 mcg/mL for Enterobacteriaceae and ≥4 mcg/mL for P. aeruginosa and A. baumannii) from the surveillance studies (SIDERO-WT-2015 and SIDERO-WT-2016) were examined using PCR and sequencing and the cefiderocol MICs determined for these isolates. Some of the isolates could carry more than one resistant determinants. Isolates could also carry nonenzymatic mechanism of resistance or enzymes that were not part of these screen (for example, the chromosomally coded β-lactamases common to S. marcescens, E. cloacae, K. aerogenes, and K. oxytoca). The results suggest that the presence of Pseudomonas extended resistant (PER) β-lactamase alone or along with oxacillinase (OXA)-23 group enzymes and New Delhi metallo-β-lactamase (NDM) enzymes in A. baumannii contributes to cefiderocol resistance (Table 75). Reduced susceptibility (or increase in MIC values) to cefiderocol was observed for P. aeruginosa containing NDM or PER β-lactamases; however, the number of isolates tested were small. Reduced susceptibility to cefiderocol was observed for Enterobacterales containing NDM carbapenemases (Table 74). In vitro, the addition of the β-lactamase inhibitors (such as avibactam, clavulanic acid, and dipicolinic acid) results in the lowering of MICs of some isolates with relatively high MICs (range 2 to 256 mcg/mL) to cefiderocol.

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Table 74. In Vitro Activity of Cefiderocol Against Molecularly Characterized Meropenem Nonsusceptible Isolates of Enterobacterales From Surveillance Studies % Isolates With % Isolates With No of MIC90 MIC Range Cefiderocol Cefiderocol MIC Source Study Pathogen/Genotype Isolates (mcg/mL) (mcg/mL) MIC ≤2 mcg/mL ≤4 mcg/mL Reference Enterobacterales Enterobacterales VIM 45 4 0.12-4 88.9 100 S-649266-EB-385-N Enterobacterales VIM 47 4 ≤0.03-8 80.9 95.7 S-649266-EF-329-N E. coli VIM 1 - 0.06 100 100 S-649266-EF-327-N K. pneumoniae VIM 2 - 0.5 100 100 S-649266-EF-327-N E. cloacae VIM 1 - 2 100 100 S-649266-EF-327-N E. cloacae GIM 1 - 4 - 100 S-649266-EF-327-N Enterobacterales NDM 33 4 0.25-8 57.6 94 S-649266-EB-385-N Enterobacterales NDM 61 8 0.25-32 41.0 72.1 S-649266-EF-329-N E. coli NDM 1 - 1 100 100 S-649266-EF-327-N K. pneumoniae NDM 2 - 2-4 50 100 S-649266-EF-327-N E. cloacae NDM 2 - 1-8 50 50 S-649266-EF-327-N Enterobacterales KPC 160 4 0.015-4 79.4 100 S-649266-EB-385-N Enterobacterales KPC 56 2 ≤0.03-8 91.1 98.2 S-649266-EF-329-N E. coli KPC-3 1 - 0.06 100 100 S-649266-EF-327-N K. pneumoniae KPC-2 3 - ≤0.03-2 100 100 S-649266-EF-327-N K. pneumoniae KPC-3 6 - 0.25-2 100 100 S-649266-EF-327-N K. pneumoniae ST512/KPC-3 25 4 0.25-4 80 100 S-649266-EF-326-N K. pneumoniae ST258/KPC-3 25 2 0.25-2 100 100 S-649266-EF-326-N Enterobacterales OXA-48 143 4 0.015-8 79.7 98.6 S-649266-EB-385-N Enterobacterales OXA-48 56 2 ≤0.03-8 92.9 98.2 S-649266-EF-329-N E. coli OXA-48 1 - 0.06 100 100 S-649266-EF-327-N K. pneumoniae OXA-48 6 - 0.06-4 83.3 100 S-649266-EF-327-N K. pneumoniae ST11/OXA-48 + CTX-M-15 25 2 ≤0.03-4 96 100 S-649266-EF-326-N K. pneumoniae ST15/OXA-48 + CTX-M-15 25 4 ≤0.03-4 88 100 S-649266-EF-326-N K. pneumoniae ST392/OXA-48 + CTX-M-15 4 - 0.06-1 100 100 S-649266-EF-326-N K. pneumoniae ST147/OXA-48 3 - 0.06-0.5 100 100 S-649266-EF-326-N E. cloacae OXA-48 1 - 0.5 100 100 S-649266-EF-327-N E. coli OXA-162 1 - 0.5 100 100 S-649266-EF-327-N K. pneumoniae OXA-162 1 - 16 0 0 S-649266-EF-327-N Enterobacterales-ESBL+ 17 4 ≤0.03-8 Not available 90 S-649266-EF-327-N E. coli ESBL+ 29 1 ≤0.03-2 100 100 S-649266-EF-311-N K. pneumoniae ESBL+ 11 4 ≤0.03-4 81.8 100 S-649266-EF-311-N K. pneumoniae ESBL+ 13 2 ≤0.03-2 100 100 S-649266-EF-326-N Enterobacterales-ESBL+ porin loss 26 4 0.06-32 61.5 88.5 S-649266-EF-329-N

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Reference ID: 4676324 NDA 209445 / S-002 Cefiderocol (Fetroja)

% Isolates With % Isolates With No of MIC90 MIC Range Cefiderocol Cefiderocol MIC Source Study Pathogen/Genotype Isolates (mcg/mL) (mcg/mL) MIC ≤2 mcg/mL ≤4 mcg/mL Reference E. coli AmpC producing 6 - ≤0.03-2 100 100 S-649266-EF-311-N Enterobacterales-AmpC + porin loss 25 2 0.06-2 100 100 S-649266-EF-329-N Enterobacterales IMP 15 2 ≤0.03-4 93.3 100 S-649266-EF-329-N Enterobacterales GES, SME, IMI 19 1 0.06-2 100 100 S-649266-EF-329-N Source: Study reports from which data was obtained is listed in the column source study reference Genotypes in red shows reduced suscept bility to cefiderocol. Abbreviations: CTX-M, cefotaximase; ESBL, extended-spectrum β-lactamase; GES, Guiana extended-spectrum β-lactamase; IMI, imipenemase; IMP, imipenemase metallo-β- lactamase; KPC, Klebsiella pneumoniae carbapenemase; MIC, minimum inhibitory concentration; NDM, New Delhi metallo-β-lactamase; OXA, oxacillinase; SME, Serratia marcescens enzyme; VIM, Verona integron-encoded metallo-β-lactamase

Table 75. In Vitro Activity of Cefiderocol Against Molecularly Characterized Meropenem Nonsusceptible Isolates of Pseudomonas aeruginosa and Acinetobacter spp. From Surveillance Studies % Isolates With % Isolates With No of MIC90 MIC Range Cefiderocol Cefiderocol MIC Source Study Pathogen/Genotype Isolates (mcg/mL) (mcg/mL) MIC ≤1mcg/mL ≤2 mcg/mL Reference P. aeruginosa IMP 12 4 0.12-4 16.6 75 S-649266-EB-385-N IMP 5 - 0.5-1 100 100 S-649266-EF-327-N IMP 25 8 0.06-16 80 80 S-649266-EF-329-N VIM, PER/VEB 1 - 1 100 100 S-649266-EB-385-N VIM 108 1 0.008-4 94.9 99 S-649266-EB-385-N VIM 10 8 0.25-8 60 90 S-649266-EF-327-N VIM 30 1 ≤0.03->128 90 93.3 S-649266-EF-329-N GIM 1 - 2 0 100 S-649266-EF-327-N NDM 2 - 2 0 100 S-649266-EF-327-N NDM 11 16 1->128 18.2 45.5 S-649266-EF-329-N GES 9 - 0.06-1 100 100 S-649266-EF-385-N GES 20 2 0.06-4 85 90 S-649266-EF-329-N PER 15 8 0.06-16 53.3 66.7 S-649266-EF-329-N VEB 10 2 0.5-8 70 90 S-649266-EF-329-N Acinetobacter spp. NDM 3 - 2-8 0 33.3 S-649266-EB-385-N NDM 20 16 1-≥128 15 50 S-649266-EF-329-N OXA-23, PER/VEB 18 >256 1->256 5.6 5.6 S-649266-EB-385-N OXA-23 693 2 ≤0.002->256 87.3 94.9 S-649266-EB-385-N OXA-23 41 16 0.06-≥128 78 85.4 S-649266-EF-329-N ST2/OXA-23 25 0.5 0.06-1 100 100 S-649266-EF-326-N

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% Isolates With % Isolates With No of MIC90 MIC Range Cefiderocol Cefiderocol MIC Source Study Pathogen/Genotype Isolates (mcg/mL) (mcg/mL) MIC ≤1mcg/mL ≤2 mcg/mL Reference OXA-23 like 4 - 0.06-0.25 100 100 S-649266-EF-327-N OXA-24, PER/VEB 40 >256 0.12->256 2.5 5.0 S-649266-EB-385-N OXA-24 222 2 0.03-8 81.1 92.4 S-649266-EB-385-N ST2/OXA-24/40 25 16 0.5-16 32 52 S-649266-EF-326-N OXA-24/40 9 - 0.25-4 66.7 88.9 S-649266-EF-329-N OXA-24-like 3 - 0.06-0.25 100 100 S-649266-EF-327-N OXA-51 19 0.5 0.06-16 94.7 94.7 S-649266-EF-329-N OXA-58 49 2 0.06-4 87.8 97.9 S-649266-EB-385-N OXA-58 10 0.25 0.06-≥128 90 90 S-649266-EF-329-N ST2/OXA-58 25 0.5 0.06-0.5 100 100 S-649266-EF-326-N ST745/OXA-58 5 - 0.06-0.25 100 100 S-649266-EF-326-N PER/VEB 61a >256 0.12->256 4.9 6.6 S-649266-EB-385-N Source: Study reports from which data was obtained is listed in the column source study reference a PER/VEB type positive carbapenem nonsusceptible Acinetobacter spp. including 58 carbapenemase-producing strains. Genotypes in red shows reduced susceptibility to cefiderocol. Abbreviations: GES, Guiana extended-spectrum β-lactamase; GIM, Germany imipenemase; IMI, imipenemase; IMP, imipenemase metallo-β-lactamase; MIC, minimum inhibitory concentration; NDM, New Delhi metallo-β-lactamase; OXA, oxacillinase; PER, Pseudomonas extended resistance; VEB, Vietnam extended-spectrum β-lactamase; VIM, Verona integron-encoded metallo-β-lactamase

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Reference ID: 4676324 NDA 209445 / S-002 Cefiderocol (Fetroja) Whole genome sequencing analyses were performed on 71 isolates (64 A. baumannii, 1 A. nosocomialis, 4 K. pneumoniae, 1 P. mirabilis, and 1 Burkholderia multivorans) with cefiderocol MICs ≥8 mcg/mL. Isolates with substitutions in the PBP1a protein, mutations or deletions in the pir-A like (ferrienterobactin receptor) and piu-like (iron carrier binding protein) genes or outer membrane porin D (oprD) gene were observed in addition to PER enzyme in A. baumannii isolates. The K. pneumoniae isolates carried OXA-48 or NDM-1 in addition to β-lactamases, variant pbp3 gene, disruption in OmpK35, and/or extended-spectrum β-lactamase (ESBL) gene. The P. mirabilis contained a temoneira (TEM)-2 gene, mutation in the siderophore uptake gene (cir-A like gene) and variant pbp3 gene. B. multivorans possessed an intrinsic PEN-A element, variations in pbp2 and pbp3 gene and mutation in the siderophore uptake gene (fiu-like gene). In general, resistance to cefiderocol in gram-negative bacteria has been associated with the presence of β-lactamases including AmpC β-lactamase overproduction, modifications of penicillin binding proteins, and mutations of transcriptional regulators that impact siderophore or efflux pump expression. Clinical isolates may produce multiple β-lactamases, or a combination of resistant determinants (ESBL, carbapenemase, porin, AmpC) that contribute to increase in cefiderocol MIC. In the original NDA, data to support the in vitro activity of cefiderocol against certain Enterobacterales genetically confirmed to contain the following: ESBLs (TEM, sulfhydryl variable [SHV], cefotaximase [CTX-M], OXA), AmpC, AmpC-type ESBL (CMY), serine- carbapenemases (such as K. pneumoniae carbapenemase [KPC], OXA-48), and metallo- carbapenemases (such as NDM and Verona integron-encoded metallo-β-lactamase [VIM]) was provided. Cefiderocol was also shown to be active in vitro against certain P. aeruginosa genetically confirmed to contain VIM, Guiana extended-spectrum β-lactamase (GES), AmpC and certain A. baumannii containing OXA-23, OXA-24/40, OXA-51, and OXA-58. Additionally, cefiderocol was shown to be active in vitro against some K. pneumoniae isolates with OmpK35/36 porin deletion and some isolates of P. aeruginosa with OprD porin deletion. The Applicant claims activity of cefiderocol against P. aeruginosa carrying imipenemase metallo-β-lactamase (IMP). The cefiderocol MICs against P. aeruginosa carrying IMP (n=42) were high and 64% isolates were susceptible at MIC of 1 mcg/mL. S. maltophilia produces two β-lactamases, metallo-carbapenemase (L1) and serine β-lactamases (L2). The cefiderocol MICs ranged from ≤0.03 to 0.25 mcg/mL, with MIC90 value of 0.25 mcg/mL for 25 isolates of S. maltophilia (study report S-649266-EF-220-R). These isolates (b) (4) were from the external validation study for the testing (b) (4) Of Novel therApeUTics), supported by the and contained both L1 and L2 β-lactamases. All isolates were meropenem and cefepime resistant and 21 out of the 25 were ceftazidime-avibactam resistant. The Applicant claims activity against A. baumannii containing AmpC and states that AmpC is produced by all A. baumannii isolates. No data was provided to support that cefiderocol does not induce AmpC β lactamases in A. baumannii. However, data on 34 clinical isolates containing AmpC with cefiderocol MIC range of 0.06 to >32 mcg/mL were provided. Whole genome sequencing of A. baumannii isolates with low susceptibility to cefiderocol revealed that all contained Acinetobacter-derived cephalosporinases (ADCs) genes which are variants of AmpC (study report S-649266-EB-331-N).

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Reference ID: 4676324 NDA 209445 / S-002 Cefiderocol (Fetroja) Activity of Cefiderocol Against Knock-Out Mutants, Porin Mutants and Efflux Pump Overproducers The original NDA included the data shown in Table 76 and Table 77 to support the activity of cefiderocol against efflux pump overproducers. It should be noted that cefiderocol MIC for the parent PAO1 varied in the two studies as the CAMHB medium supplemented with apotransferrin (20 micromol/L) was used in the experiments used to generate results depicted in Table 76 and ID-CAMHB medium was used to generate results depicted in Table 74. The cefiderocol MICs against P. aeruginosa strains with knockout mutations, PW8599 (piuA), PW8601 (piuC), and SR-L00001 (piuA and piuC), were several fold higher (2 mcg/mL) than that against parent strain PAO1 (0.031 mcg/mL) (report S-649266-EB-191-N). As the four-fold increase observed for the knockout mutants in ampD, mexF, mexR and nfxB (0.125 mcg/mL) compared to the parent strain PAO1 (0.031 mcg/mL) were in the susceptible range (0.031 to 0.125 mcg/mL), the Applicant concludes that the cefiderocol activity was not affected by the mutations in mexR or nfxB (strain PW1777 or PW8753) and consequent overexpression of efflux pumps MexAB-OprM or MexCD-OprJ, respectively (Table 76). The Applicant states that the ceftazidime and cefepime MICs against the mutants of mexR (strain PW1777) or ampD (strain PW8615), which caused overproduction of efflux pump MexAB-OprM or AmpC, respectively were eight-fold higher (4 to 16 mcg/mL) compared to susceptible range (0.5 to 2 mcg/ml). The cefiderocol MICs against mutant strain OFR 504 which is deficient in MexA-MexB-OprM but was stated to overproduce OprJ was four-fold lower (≤0.031 mcg/mL) than parent PAO1 strain (0.125 mcg/mL) in these experiments (Table 77). OprJ may enhance the permeability of the P. aeruginosa outer membrane to cefiderocol as a porin. Due to the variability in cefiderocol MICs as a result of the different medium used in the two studies (MIC of 0.031 mcg/mL in Table 76 and 0.125 mcg/ml in Table 77), it is difficult to compare results across studies. Cefiderocol MIC against OprD deficient mutant was similar to that of the parent strain while that of imipenem (IPM) which uses porin to cross the outer membrane was eight-fold higher than the parent strain. In the case of efflux pump OprM overexpressing strain SO20, the MIC of aztreonam (AZT) which uses the OprM to discharge the drug was higher than the parent strain. However, MICs for ceftazidime, IPM, cefepime were not impacted in this OprM overproducing strain.

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Table 76. Antibacterial Activity Against the Mutant Strains of P. aeruginosa PAO1 (EB-191-N)

Source: Study S-649266-EB-191-N The shaded cells show the MIC values out of the susceptible range Abbreviations: MIC, minimum inhibitory concentration

Table 77. Antibacterial Activity Against the Mutant Strains of P. aeruginosa PAO1 (EB-204-N)

Source: Study Report S-649266-EB-204-N Table 15. Abbreviations: AZT, aztreonam; CAZ, ceftazidime; CPFX, ciprofloxacin; IPM, imipenem The increase in MIC in relation to AmpC overexpression or MexAB-OprM or MexCD-OprJ efflux overexpression due to knockout of ampD, mexR or nfxB were four fold but within the susceptible range. The mutation of nfxB may suppress efflux system(s) other than MexAB- OprM and MexXY-OprM. The new data in this submission included cefiderocol MICs for well characterized clinical isolates of K. pneumoniae, P. aeruginosa and A. baumannii (study report S-649266-EF-313-N). In this study, correlation of cefiderocol MIC values to the presence of β-lactamases and genetic expression of blaKPC, ompK35, ompK36 and arcB in 34 K. pneumoniae clinical isolates, the genetic expression of ampC, oprD, mexA, mexC, mexE and mexX in 33 P. aeruginosa clinical isolates, and the genetic expression of ampC, oxa51, adeB, and abeM in 34 A. baumannii clinical

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Reference ID: 4676324 NDA 209445 / S-002 Cefiderocol (Fetroja) isolates were analyzed using two-tailed student’s t-test and multiple linear regression analysis. A p-value<0.05 in this analyses was considered significant. The cefiderocol MIC range for K. pneumoniae isolates containing the carbapenemase KPC was 0.06 to 0.5 mcg/mL (Table 78). The cefiderocol MIC range for K. pneumoniae isolates containing only an ESBL (blaSHV) was 0.25 to 4 mcg/mL. The one isolate in this group with a cefiderocol MIC of 4 mcg/mL also possessed an AmpC-type (ACT-1) enzyme. The authors conclude that there was no correlation between cefiderocol MICs and expression of the blaKPC, the efflux-related genes marA, ramA, soxS, and acrB, and the porin-related genes ompK35 or ompK36.

Table 78. Antibacterial Activity of Cefiderocol and Expression Level of Resistance Related Genes in Clinical Isolates of K. pneumoniae

Source: S-649266-EF-313-N Abbreviations: MIC, minimum inhibitory concentration P. aeruginosa isolates with increased ampC expression (>10 time control) had modestly higher cefiderocol MICs compared to isolates without increased expression of this enzyme (0.67±1.01 versus 0.27±0.23 mcg/mL, p =0.2) (Table 79). The presence of multiple resistant determinant expression results in higher cefiderocol MIC compared to isolates with high expression of single efflux, porin or ampC gene. The authors state that there was no correlation between cefiderocol MICs and expression of ampC mexA, mexC, mexE, mexX, and oprD in P. aeruginosa.

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Table 79. Antibacterial Activity of Cefiderocol and Expression Level of Resistance Related Genes in Clinical Isolates of P. aeruginosa

Source: S-649266-EF-313-N Abbreviations: MIC, minimum inhibitory concentration A. baumannii isolates containing an SHV ESBL had significantly higher cefiderocol MICs than isolates without ESBLs (8.04±11.58 versus 0.86±1.08 mcg/mL, p=0.02) (Table 80). The authors conclude that there was no correlation between cefiderocol MICs and expression of genes encoding ampC, blaOXA-51, and the efflux systems adeB and abeM in A. baumannii based on regression analysis (p=0.02).

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Table 80. Antibacterial Activity of Cefiderocol and Expression Level of Resistance Related Genes in Clinical Isolates of A. baumannii

Source: S-649266-EF-313-N Abbreviations: MIC, minimum inhibitory concentration The Applicant further analyzed the relationship between AZT MIC and MexA expression level in P. aeruginosa using published data (Figure 16). The Applicant concluded that AZT MIC are high in the isolates which showed higher expression level of MexA while cefiderocol retained low MIC against these isolates and the efflux pump MexAB-OprM in P. aeruginosa does not contribute to MIC increases of cefiderocol.

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Figure 16. Relationship Between the Expression Level of MexA and MIC of Aztreonam (A) or Cefiderocol (B) Against P. aeruginosa

Source: Figure 17 in section 2.7.2.4 Addendum-HABP/VABP of the Application Abbreviations: MIC, minimum inhibitory concentration The authors and Applicant conclude that there is no significant correlation between cefiderocol MICs and the expression level of resistance determinants such as efflux pumps (AcrB of K. pneumoniae, and MexA, MexC, MexE and MexX of P. aeruginosa, and AdeB and AbeM of A. baumannii) and porins (OmpK35, OmpK36 of K. pneumoniae, and OprD of P. aeruginosa). Cefiderocol was shown to be active against K. pneumoniae with ompK35/36 porin mutation and P. aeruginosa with oprD porin mutation previously (original NDA).

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Reference ID: 4676324 NDA 209445 / S-002 Cefiderocol (Fetroja) Both high and low levels of resistance are associated with overproduction of the pumps, with additional resistance mechanisms required for high-level resistance. The β-lactam resistance in clinical isolates of K. pneumoniae, P. aeruginosa and A. baumannii is a result of the interplay between multiple resistance mechanisms. In P. aeruginosa, it is the result of interplay between diminished production of OprD, increased activity of AmpC, and several efflux systems. Simultaneous expression of more than one efflux systems can cause misinterpretation of the substrate specificity of each multidrug efflux system. Multiple-knockout experiments, use of isogenic strains, and direct measurements of efflux are necessary to elucidate the actual substrate specificities of the different efflux pumps. The multiple regression analyses performed by the authors do not address assumptions made regarding interactions between different resistant determinants as differences in presence of β-lactamases, membrane permeability impacting influx can confound the results. The analyses have limited sensitivity as only large changes in efflux can be detected in the presence of select β-lactamases and porin expression. Use of appropriate methodology is important to allow for drawing conclusions on efflux activity. Cross-Resistance Cross-resistance of cefiderocol with other classes of antibacterial drugs has not been identified; therefore, isolates resistant to other antibacterial drugs may be susceptible to cefiderocol. In the surveillance study conducted in 2018, 72 gram-negative isolates had cefiderocol MIC >4 mcg/mL(study report S-649266-EF-308-N). The cross-resistance between cefiderocol and cefepime or meropenem is observed for majority of the A. baumannii isolates (Table 81). In the case of Enterobacterales, cross-resistance between cefiderocol and cefepime, ceftazidime- avibactam, or ceftolozane-tazobactam was observed in approximately 40 to 50% isolates.

Table 81. In Vitro Activity of Cefiderocol and Comparators Against 72 Gram-Negative Clinical Isolates With Cefiderocol MICs of >4 mcg/mL Using CLSI Breakpoints Organism (N) Compound Breakpoint %I %R MIC90 MIC Range A. baumannii (50) Cefiderocol ≤4 | 8 | ≥16 6.0 94.0 >256 8->256 Aztreonam-avibactam No breakpoints na na >8 8->8 Cefepime ≤8 | 16 | ≥32 0.0 98.0 >64 8->64 Ceftazidime-avibactam No breakpoints na na >64 16->64 Ceftolozane-tazobactam No breakpoints na na >64 ≤0.06->64 Ciprofloxacin ≤1 | 2 | ≥4 0.0 98.0 >8 1->8 Colistin ≤2 | -- | ≥4 0.0 2.0 2 0.5->8 Meropenem ≤2 | 4 | ≥8 0.0 78.0 >64 0.5->64 Meropenem-vaborbactam No breakpoints na na >64 0.25->64 E. cloacae (2) Cefiderocol ≤4 | 8 | ≥16 100 0 -- 8-8 Aztreonam-avibactam No breakpoints na na -- 0.5->8 Cefepime ≤2 | 4-8 | ≥16 0 100 -- >64->64 Ceftazidime-avibactam ≤8 | -- | ≥16 0.0 50.0 -- 4-16 Ceftolozane-tazobactam ≤2 | 4 | ≥8 0 100 -- 32-32 Ciprofloxacin ≤0.25 | 0.5 | ≥1 0.0 50.0 -- 0.25->8 Colistin ≤2 | -- | ≥4 (EUCAST) 0 0 -- 0.5-1 Meropenem ≤1 | 2 | ≥4 0.0 50.0 -- ≤0.06-32 Meropenem-vaborbactam ≤4 | 8 | ≥16 0.0 50.0 -- ≤0.06-16 E. coli (2) Cefiderocol ≤4 | 8 | ≥16 50.0 50.0 -- 8-32 Aztreonam-avibactam No breakpoints na na -- ≤0.12-2 Cefepime ≤2 | 4-8 | ≥16 0 100 -- 16->64 166 Integrated Review Template, version date 2019/10/16

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Organism (N) Compound Breakpoint %I %R MIC90 MIC Range Ceftazidime-avibactam ≤8 | -- | ≥16 0.0 50.0 -- 0.25->64 Ceftolozane-tazobactam ≤2 | 4 | ≥8 0.0 50.0 -- 0.5->64 Ciprofloxacin ≤0.25 | 0.5 | ≥1 0 100 -- 8->8 Colistin ≤2 | -- | ≥4 (EUCAST) 0 0 -- ≤0.25-0.5 Meropenem ≤1 | 2 | ≥4 0.0 50.0 -- ≤0.06-64 Meropenem-vaborbactam ≤4 | 8 | ≥16 0.0 50.0 -- ≤0.06-64 K. aerogenes (1) Cefiderocol ≤4 | 8 | ≥16 100 0 -- 8-8 Aztreonam-avibactam No breakpoints na na -- ≤0.12-≤0.12 Cefepime ≤2 | 4-8 | ≥16 0 0 -- 0.25-0.25 Ceftazidime-avibactam ≤8 | -- | ≥16 0 0 -- 0.5-0.5 Ceftolozane-tazobactam ≤2 | 4 | ≥8 100 0 -- 4-4 Ciprofloxacin ≤0.25 | 0.5 | ≥1 0 0 -- ≤0.12-≤0.12 Colistin ≤2 | -- | ≥4 (EUCAST) 0 0 -- 0.5-0.5 Meropenem ≤1 | 2 | ≥4 0 0 -- ≤0.06-≤0.06 Meropenem-vaborbactam ≤4 | 8 | ≥16 0 0 -- ≤0.06-≤0.06 K. pneumoniae (5) Cefiderocol ≤4 | 8 | ≥16 60.0 40.0 -- 8-128 Aztreonam-avibactam No breakpoints na na -- 0.5-1 Cefepime ≤2 | 4-8 | ≥16 0 100 -- 32->64 Ceftolozane-tazobactam ≤2 | 4 | ≥8 0 100 -- >64->64 Ciprofloxacin ≤0.25 | 0.5 | ≥1 0 100 -- >8->8 Colistin ≤2 | -- | ≥4 (EUCAST) 0.0 20.0 -- 0.5-8 Meropenem ≤1 | 2 | ≥4 0 100 -- 8->64 Meropenem-vaborbactam ≤4 | 8 | ≥16 0.0 80.0 -- 4->64 P. mirabilis (2) Cefiderocol ≤4 | 8 | ≥16 0 100 -- 128-256 Aztreonam-avibactam No breakpoints na na -- 0.5->8 Cefepime ≤2 | 4-8 | ≥16 50.0 50.0 -- 4->64 Ceftazidime-avibactam ≤8 | -- | ≥16 0.0 50.0 -- 4-32 Ceftolozane-tazobactam ≤2 | 4 | ≥8 0 100 -- 8-32 Ciprofloxacin ≤0.25 | 0.5 | ≥1 0.0 50.0 -- 0.25->8 Colistin ≤2 | -- | ≥4 (EUCAST) 0 100 -- >8->8 Meropenem ≤1 | 2 | ≥4 0 0 -- ≤0.06-0.25 Meropenem-vaborbactam ≤4 | 8 | ≥16 0 0 -- 0.12-0.25 S. marcescens (2) Cefiderocol ≤4 | 8 | ≥16 50.0 50.0 -- 8-128 Aztreonam-avibactam No breakpoints na na -- 0.5-2 Cefepime ≤2 | 4-8 | ≥16 0 100 -- >64->64 Ceftazidime-avibactam ≤8 | -- | ≥16 0 100 -- >64->64 Ceftolozane-tazobactam ≤2 | 4 | ≥8 0 100 -- >64->64 Ciprofloxacin ≤0.25 | 0.5 | ≥1 100 0 -- 0.5-0.5 Colistin ≤2 | -- | ≥4 (EUCAST) 0 100 -- >8->8 Meropenem ≤1 | 2 | ≥4 0 100 -- 64->64 Meropenem-vaborbactam ≤4 | 8 | ≥16 0 100 -- 64->64 Source: Study S-649266-EF-308-N Table 17. MIC90, and Range in mcg/mL, avibactam and tazobactam tested at a fixed concentration of 4 mcg/mL Vaborbactam tested at a fixed concentration of 8 mcg/mL MIC90 not calculated for n ≤10. Abbreviations: CLSI, Clinical and Laboratory Standards Institute; I, intermediate; MIC, minimum inhibitory concentration; na, no available breakpoints; R, resistant

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Reference ID: 4676324 NDA 209445 / S-002 Cefiderocol (Fetroja) Enterobacter cloacae complex isolates (n=2) with amino acid deletion in the R2 loop of AmpC β-lactamase were concurrently resistant to ceftazidime-avibactam, cefepime and cefiderocol (Kawai et al. 2020; Shields et al. 2020). In Vivo Activity The activity of cefiderocol against 24 S. maltophilia (cefiderocol MIC range 0.015 to 0.5 mg/mL) was examined in the neutropenic murine thigh infection model (report S-649266- EF-353-R). The thighs of mice were inoculated with 108 CFU/mL and treatment with human simulated dose of cefiderocol (2 gm q8H 3-hour infusion) and ceftazidime (2 gm q8H 2-hour infusion) was initiated 2 hours postinfection. Bacterial reduction of ≥2 log-reduction was achieved in 21 isolates (87.5%) and ≥1 log-reduction was achieved in the remaining three isolates (12.5%) at 24 hours in cefiderocol treated mice (Figure 17).

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Figure 17. Efficacy of 24 Hours of a Cefiderocol Human-Simulated Regimen (2 g q8h, 3-Hour Infusion) and a Ceftazidime Human-Simulated Regimen (2 g q8h, 2-Hour Infusion) Against Ceftazidime-Susceptible (A) and Ceftazidime-Resistant (B) S. maltophilia in Neutropenic Murine Thigh Infection Model

Source: S-649266-EF-353-R, Figure 2. * Indicate statistically significant differences (p≤0.05) between cefiderocol and ceftazidime Abbreviations: CFU, colony forming units; MIC, minimum inhibitory concentration; q8h, every 8 hours; STM, S. maltophilia The activity of cefiderocol was examined in the iron overloaded murine thigh infection model to evaluate the effects of iron overload (report S-649266-EF-347-R). The neutropenic thigh

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Reference ID: 4676324 NDA 209445 / S-002 Cefiderocol (Fetroja) infection model were treated with iron dextran 100 mg/kg daily for 14 days to load iron. Mice were infected with 31 strains of gram-negative bacteria, including E. coli, K. pneumoniae, P. aeruginosa, and A. baumannii and treated with cefiderocol human-simulated regimen. For individual isolates treated with cefiderocol (Figure 18), significant differences in efficacy between models were observed in one P. aeruginosa strain PSA 1588, with growth in the standard model and killing in the iron overloaded model. Cefiderocol was active against gram negative bacteria in the presence of iron overload.

Figure 18. Efficacy of 24 Hours of a Cefiderocol Human-Simulated Regimen (HSR) (2 g q8h, 3-Hour Infusion) Against E.coli and K. pneumoniae (A), A. baumannii (B), and P. aeruginosa (C) in Standard and Iron Overloaded Murine Thigh Infection Models

Source: S-649266-EF-347-R, Figure 2. * Isolates for which cefiderocol had a significantly different change in log10 CFU/thigh between standard and iron overloaded models Abbreviations: CFU, colony forming unit; MIC, minimum inhibitory concentration; q8h, every 8 hours

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Reference ID: 4676324 NDA 209445 / S-002 Cefiderocol (Fetroja) Data on molecular characterization of isolates previously tested in the murine neutropenic thigh model were included in this submission (report S-649266-EF-231-R amended). These data were also provided during labeling negotiations for the original NDA (Figure 19, Figure 20 and Figure 21).

Figure 19. Bacterial Reduction Against Each Isolate of Enterobacteriaceae in Murine Thigh Infection Models Under Humanized PK of Cefiderocol

Source: Study Report S-649266-EF-231-R Appendix D. Each * represents the number of times the isolate was repeated. All repeat data were averaged together. EC 462 contained the cephalosporinase CMY-42 and EC 455 contained the cephalosporin CMY-2 in addition to NDM Abbreviations: CFU, colony forming unit; MIC, minimum inhibitory concentration; PK, pharmacokinetics

Figure 20. Bacterial Reduction Against Each Isolate of P. aeruginosa in Murine Thigh Infection Models Under Humanized PK of Cefiderocol

Source: Study Report S-649266-EF-231-R Appendix F. Each * represents the number of times the isolate was repeated. All repeat data were averaged together. Abbreviations: CFU, colony forming unit; MIC, minimum inhibitory concentration; PK, pharmacokinetics

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Figure 21. Bacterial Reduction Against Each Isolate of A. baumannii in Murine Thigh Infection Models Under Humanized PK of Cefiderocol

Source: Study Report S-649266-EF-231-R Appendix E. Each * represents the number of times the isolate was repeated. All repeat data were averaged together. Abbreviations: CFU, colony forming unit; MIC, minimum inhibitory concentration; PK, pharmacokinetics The study shows that the human simulated cefiderocol dosing is active against Enterobacteriaceae, A. baumannii, and P. aeruginosa including some carbapenemase-producing isolates with cefiderocol MICs of ≤4 mcg/mL and S. maltophilia isolates with MICs ≤0.5 mcg/mL in the neutropenic thigh infection model. It should be noted that isolates with range of cefiderocol MIC were selected to assess the in vivo activity based on the PK-PD target attainment using the humanized dosing regimen. Discordance between in vitro and in vivo activity against metallo−β-lactamases has been reported previously (MacVane et al. 2014; Zmarlicka et al. 2015). The in vivo mouse model can overestimate the activity of the drug against bacteria containing metallo−β-lactamases as drugs without in vitro activity against metallo−β-lactamases are active in vivo. The in vivo data confirms the in vitro resistance observed in A. baumannii strains carrying the PER gene. There is minimum data available against other genotypes. Previous studies have shown regrowth of bacteria with increase in MIC in 3 of 15 isolates with cefiderocol MICs <8 mcg/mL with humanized dosing. Key findings from data submitted in the original NDA include the following: • In an immunocompetent rat pneumonia model, reduction in bacterial counts in the lungs of animals infected with K. pneumoniae with MICs ≤8 mcg/mL and P. aeruginosa with MICs ≤1mcg/mL was observed using humanized cefiderocol dose. The Applicant would like to claim activity of cefiderocol against S. maltophilia with MICs ≤0.5 mcg/mL and A. baumannii with MICs ≤2 mcg/mL in the immunocompetent rat infection model based on studies submitted in the original NDA summarized below: Immunocompetent Rat Lung Infection Model The activity of cefiderocol was evaluated against three P. aeruginosa (two MDR strain), five A. baumannii (two MDR strains, one OXA-23 strain), three NDM-1-producing K. pneumoniae, four KPC-producing K. pneumoniae, and two S. maltophilia strains in the immunocompetent rat 172 Integrated Review Template, version date 2019/10/16

Reference ID: 4676324 NDA 209445 / S-002 Cefiderocol (Fetroja) lung infection model [study reports 2014N197096_01, S-649266-EF-299-N, S-649266-EB-157- N and S-649266-EB-303-N]. Rats were infected via intratracheal instillation of bacteria in molten agar. The cefiderocol human plasma exposure profiles were simulated in these studies and treatment was initiated at 1-hour postinfection for mice infected with A. baumannii and K. pneumoniae and 2 hours postinfection for P. aeruginosa. Cefiderocol 2 g was administered intravenously thrice a day as a 1-hour or 3-hour infusion for 4 days. The bacterial burden in the lungs were measured at the EOT. These studies suggest that 3-hour infusion provides greater bacterial burden control than 1-hour infusion (Table 82). Although a >2 log reduction was observed in cefiderocol treated rats infected with S. maltophilia, very little growth/replication was observed in untreated control over the 96 hours of study duration (shaded cells, Table 71). Similar observations were made with some A. baumannii and K. pneumoniae strains (shaded cells, Table 82).

Table 82. Summary of in Vivo Efficacy Studies Using Immunocompetent Rat Lung Infection Model Cefiderocol Test Organisms Resistance MIC (mcg/mL) Result P. aeruginosa ATCC 27853 - 0.25 >3 log10 reduction in bacterial (104 CFU/rat) burden in the lungs. Activity was similar to ceftazidime. P. aeruginosa SR27001 MDRP (IMP-1); 1.0 3 log10 reduction in bacterial (104 CFU/rat) CAZ MIC >64 burden in the lungs. Activity was mcg/mL superior to ceftazidime. P. aeruginosa SR24888 MDRP (IMP-1) 0.25 3 log10 reduction in bacterial (105 CFU/rat) MEPM MIC >64 burden in the lungs. Activity was mcg/mL, colistin MIC superior to meropenem and 0.6 mcg/mL colistin. A. baumannii 1484911 CC92; 0.25 ~2 log10 reduction in bacterial (106CFU/rat) CAZ MIC >32 burden in the lungs 3 -- and 1- mcg/mL hour infusions. Activity was superior to ceftazidime. A. baumannii 1485176 MDRA (CC92); 0.125 3 log10 reduction in bacterial (106 CFU/rat) CAZ and MEPM MIC burden in the lungs with 3- and ≥32mcg/mL 1-hour infusions. Activity was superior to ceftazidime. 2 untreated controls mice showed decrease in bacterial burden or no change in bacterial burden at 96 hours. A. baumannii 1515988 Ceftazidime resistant 0.125 ≥3 log10 reduction in bacterial (106 CFU/rat) CAZ MIC >32 burden in the lungs with 3- and mcg/mL 1-hour infusions. Activity was superior to ceftazidime and similar to meropenem. 1 log10.growth of untreated controls at 96 hours. And no change in bacterial burden in 1 of 4 mice. A. baumannii 1485247 MDRA; 2.0 3 log10 reduction in bacterial (106 CFU/rat) CAZ MIC >32 burden in the lungs with 3-hour mcg/mL and MEPM infusion. Activity was superior to MIC 8 mcg/mL ceftazidime. 1 log10.growth of untreated controls at 96 hours.

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Cefiderocol Test Organisms Resistance MIC (mcg/mL) Result A. baumannii Ab13 MDRA, OXA-23 0.125 2.5 log10 reduction in bacterial (105 CFU/rat) MEPM MIC 64 burden in the lungs. Activity was mcg/mL superior to meropenem K. pneumoniae VA-384 KPC-2 0.25 3 log10 reduction with 3-hour (106 CFU/rat) CAZ and MEPM MIC infusion. No reduction with 1- >32mcg/mL hour infusion or meropenem. Bacterial growth in untreated controls was 0.5 log 10 at 96 hours. K. pneumoniae VA-361 KPC-2 0.25 3 log10 reduction with 3-hour 6 (10 CFU/rat) CAZ MIC >32 infusion. 1 log10 reduction with 1- mcg/mL and MEPM hour infusion. No reduction with MIC 16 mcg/mL ceftazidime K. pneumoniae K12 NDM-1; 0.25 3 log10 reduction with 3 hour and (106 CFU/rat) CAZ and MEPM MIC 1-hour infusion. No reduction >32mcg/mL with ceftazidime K. pneumoniae NCTC 13443 NDM-1; 2.0 ≥3 log10 reduction with 3-hour 6 (10 CFU/rat) CAZ and MEPM MIC infusion. 1 log10 reduction with 1- >32mcg/mL hour infusion. No reduction with meropenem K. pneumoniae VA-391 KPC-3 ≤0.125 >3 log10 reduction with 3-hour 6 (10 CFU/rat) CAZ MIC >32 infusion and 2 log10 reduction mcg/mL and MEPM with 1-hour infusion. No 16 mcg/mL reduction with ceftazidime. Bacterial growth in untreated controls was minimal at 96 hours. K. pneumoniae OMA3 NDM-1, 1.0 ~2 log10 reduction with 1-hour (105 CFU/rat) CTX-M-15, infusion. Activity superior to carbapenem meropenem and colistin resistant MEPM MIC 64 mcg/mL K. pneumoniae SR08651 Carbapenem 2.0 ~2 log10 reduction with 1-hour (105 CFU/rat) resistant, KPC, SHV infusion. Activity superior to MEPM MIC >64 meropenem and colistin mcg/mL S. maltophilia 1373179 - - Not interpretable; no increase in (6.6 x105 CFU/rat) bacterial burden in the lungs of control rats. S. maltophilia 1444466 MEPM MIC =64 0.06 >2 log10 reduction observed with (2.6 x106 CFU/rat mcg/mL 3-hour infusion. No reduction with meropenem. However, <1 log10 increase in CFU/untreated controls mice was observed at 96 hours compared to start of treatment in 3 of 4 mice with data.

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Cefiderocol Test Organisms Resistance MIC (mcg/mL) Result S. maltophilia 1476057 MEPM MIC =128 0.5 >2 log10 reduction observed with (3.3 x106 CFU/rat mcg/mL 3-hour infusion. No reduction with meropenem. However, only 0.5log10 increase in CFU/untreated controls mice was observed at 96 hours compared to start of treatment. Study Reports 2014N197096_01, S-649266-EF-299-N, S-649266-EB-157-N and S-649266-EB-303-N Abbreviations: CAZ, ceftazidime; CFU, colony-forming unit; CTX-M, cefotaximase; IMP, imipenemase metallo-β-lactamase; KPC, Klebsiella pneumoniae carbapenemase; NDM-1, New Delhi metallo-beta-lactamase 1; MDRA, multidrug resistant A. baumannii; MDRP, multidrug resistant P. aeruginosa; MEPM, meropenem; MIC, minimum inhibitory concentration; SHV, sulfhydryl variable It appears that some strains of A. baumannii and K. pneumoniae may not be fit for use in this model. Variability was observed in the 96-hour saline untreated controls, making it difficult to interpret the log reduction attributable to cefiderocol treatment. The 3-hour infusion of cefiderocol appears to have an effect on immunocompetent rats infected with A. baumannii strains. Several studies that used S. maltophilia to infect the lungs of mice or rats did not document significant increases in bacterial numbers postinoculation; rather, bacterial burden declined postinoculation (Di Bonaventura et al. 2010; Rouf et al. 2011). The role of the rat lung infection model for determination of activity against S. maltophilia is unclear: • In an immunocompetent murine urinary tract infection model, cefiderocol reduced bacterial counts in the kidneys of mice infected with E. coli, K. pneumoniae, and P. aeruginosa isolates with MICs ≤1 mcg/mL. • In an immunocompromised murine systemic infection model, cefiderocol increased survival in mice infected with E. cloacae, S. maltophilia, and B. cepacia isolates with MICs ≤0.5 mcg/mL compared to untreated mice. In an immunocompetent murine systemic infection model, cefiderocol increased survival in mice infected with S. marcescens and P. aeruginosa isolates with MICs ≤1 mcg/mL compared to untreated mice. Clinical Study Additional microbiological assessments conducted for the breakpoint determination include an assessment at TOC by baseline pathogen and cefiderocol MIC (Table 83).

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Table 83. Summary of Clinical Cure and Microbiological Eradication at Test-of-Cure (TOC) Per Baseline Pathogen and Minimum Inhibitory Concentration Values in the Modified Intention-to- Treat Population Cefiderocol N=145 Microbiological Cefiderocol Clinical Cure at TOC Eradication at TOC Baseline Pathogen MIC (mcg/mL) n/N’ (%) n/N’(%) K. pneumoniae (n=48) ≤0.03 5/8 (62.5) 3/8 (37.5) 0.06 1/3 (33.3) 1/3 (33.3) 0.12 1/1 (100.0) 1/1 (100.0) 0.25 3/6 (50.0) 3/6 (50.0) 0.5 5/9 (55.6) 4/9 (44.4) 1 9/9 (100.0) 7/9 (77.8) 2 6/9 (66.7) 3/9 (33.3) 4 1/2 (50.0) 0/2 MIC range ≤0.03 to 4 31/47(66) 22/47 (46.8) MIC90 2 - - E. coli (n=19) ≤0.03 4/5 (80.0) 3/5 (60.0) 0.06 3/4 (75.0) 2/4 (50.0) 0.12 2/2 (100.0) 2/2 (100.0) 0.25 0/2 0/2 0.5 1/4 (25.0) 1/4 (25.0) 1 2/2 (100.0) 2/2 (100.0) MIC range ≤0.03 to 1 12/19 (63.2) 10/19 (52.6) MIC90 0.5 S. marcescens (n=8) ≤0.03 1/1 (100.0) 1/1 (100.0) 0.06 0/1 0/1 0.12 0/1 0/1 0.25 4/4 (100.0) 3/4 (75.0) 0.5 0/1 0/1 MIC range ≤0.03 to 0.5 5/8 (62.5) 4/8 (50.0) MIC90 0.25 E. cloacae (n=7) 0.06 1/1 (100.0) 1/1 (100.0) 0.5 2/3 (66.7) 2/3 (66.7) 1 1/2 (50.0) 0/2 2 1/1 (100.0) 1/1 (100.0) MIC range 0.06 to 2 5/7 (71.4) 4/7 (57.1) MIC90 - E. aerogenes (n=4) 0.06 0/3 0/3 1 1/1 (100.0) 1/1 (100.0) MIC range 0.06 to 1 1/4 (25.0) 1/4 (25.0) MIC90 - M. catarrhalis (n=2) ≤0.03 1/1 (100.0) 0/1 0.25 1/1 (100.0) 1/1 (100.0) MIC range ≤0.03 to 0.25 2/2 (100.0) 1/2 (50.0) MIC90 - P. mirabilis (n=2) ≤0.03 1/2 (50.0) 1/2 (50.0) K. oxycota (n=2) ≤0.03 1/1 (100.0) 1/1 (100.0) 0.06 0/1 0/1 MIC range ≤0.03 to 0.06 1/2 (50.0) 1/2 (50.0) MIC90 -

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Cefiderocol N=145 Microbiological Cefiderocol Clinical Cure at TOC Eradication at TOC Baseline Pathogen MIC (mcg/mL) n/N’ (%) n/N’(%) C. koseri (n=1) 0.5 1/1 (100.0) 1/1 (100.0) C. fruendii (n=1) 0.5 0/1 0/1 M. morganii (n=1) 0.06 0/1 0/1 P. aeruginosa (n=24) ≤0.03 1/1 (100.0) 1/1 (100.0) 0.06 2/3 (66.7) 2/3 (66.7) 0.12 4/7 (57.1) 1/7 (14.3) 0.25 5/7 (71.4) 2/7 (28.6) 0.5 2/4 (50.0) 2/4 (50.0) 1 2/2 (100.0) 1/2 (50.0) MIC range ≤0.03 to 1 16/24 (66.7) 9/24 (37.5) MIC90 0.5 - - A. baumannii (n=23) ≤0.03 1/1 (100.0) 1/1 (100.0) 0.12 1/4 (25.0) 1/4 (25.0) 0.25 2/4 (50.0) 2/4 (50.0) 0.5 4/6 (66.7) 2/6 (33.3) 1 2/2 (100.0) 1/2 (50.0) 2 1/3 (33.3) 1/3 (33.3) 4 0/1 0/1 >64 1/1 (100.0) 1/1 (100.0) MIC range ≤0.03 to >64 12/22 (54.5) 9/22 (40.9) MIC90 2 A. nososcomialis (n=2) 0.25 1/2 (50.0) 1/2 (50.0) A. pitti (n=1) 0.5 1/1 (100.0) 1/1 (100.0) S. maltophilia (n=1) 0.25 1/1 (100.0) 1/1 (100.0) B. cepacia (n=1) ≤0.03 1/1 (100.0) 1/1 (100.0) Source: Table 14.2.8.1.2 and Table 14.2.9.1.2 Study Report 1615R2132 Amendment 1. Percentage is calculated using N’ Abbreviations: N, total number of subjects in mITT population; N’, the number of baseline pathogens at the given MIC level; n, the number (%) of microbiological eradication at Test of Cure for the baseline pathogen at the given MIC level; MIC90, minimum inh bitory concentration required to inh bit 90% of isolates; MIC, minimum inhibitory concentration; mITT, modified-intention-to-treat The ACM by baseline resistant determinants in isolates that were meropenem resistant is shown in Table 84. Multiplex PCR with some sequencing was carried out using meropenem-resistant isolates collected in the APEKS-NP study. Enterobacterales isolates were screened for the presence of bla encoding ESBLs (TEM, SHV, five subtypes of CTX-Ms including CTX-M-1- group, CTX-M-2-group, CTX-M-8-group, CTX-M-9-group, and CTX-M-25-group, VEB, PER, GES), plasmid-encoded AmpC β-lactamases (ACC, ACT, CMY, DHA, FOX, MIR, MOX), and carbapenemases (KPC, OXA-48-like, IMP, VIM, NDM, SPM, and GIM). P. aeruginosa isolates were screened for the presence of bla encoding ESBLs, plasmid encoded AmpC β-lactamases and the chromosomally-encoded pseudomonal AmpC β-lactamase (PDC), and carbapenemases (KPC, OXA-24/40-like, IMP, VIM, NDM, SPM, and GIM). Acinetobacter baumannii isolates were screened for the presence of bla encoding ESBLs and carbapenemases (OXA-23-like, OXA-24/40-like, OXA-48-like, OXA-58-like, KPC, IMP, VIM, NDM, and SPM). The porin genes found in K. pneumoniae (ompK35 and ompK36), E. cloacae (ompF and ompC), P. aeruginosa (oprD) and A. baumannii (oprD and carO) were amplified and sequenced. P. aeruginosa mexB, mexD, mexF, and mexY transcript (mRNA) levels were normalized to transcript levels of the ribosomal gene rpsL

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Reference ID: 4676324 NDA 209445 / S-002 Cefiderocol (Fetroja) and compared to transcript levels observed for the reference strain PAO 1. A. baumannii oprD and carO transcript levels were normalized to 16S RNA and compared to transcript levels observed for the reference strain ATCC 19606.

Table 84. Mortality in Meropenem Resistant Isolates by Baseline Resistant Determinants

Source: Table 2.20.3 in ISS/ISE. [a] Treatment difference (cefiderocol minus meropenem) is the estimate of the difference in the all-cause mortality rate at each timepoint between the 2 treatment arms. Abbreviations: ACM, all-cause mortality; EOS, end of study; N', number of subjects with each baseline resistance mechanism and known survival outcome at each time point

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Reference ID: 4676324 NDA 209445 / S-002 Cefiderocol (Fetroja) 19. Other Drug Development Considerations Additional Information

Not applicable. 20. Data Integrity-R Consults (OSI, Other Inspections)

Not applicable. 21. Labeling Summary of Considerations and Key Additional Information

21.1. Prescribing Information Key modifications to the proposed labeling submitted on March 27, 2020, are described in Table 85. Consultations were obtained from the Office of Prescription Drug Promotion (OPDP) and the Division of Cardiorenal Products (DCRP) who provided recommendations on CRRT dosing information.

Table 85. Summary of Key Labeling Modifications Applicant’s Modification Section Proposed in Labeling Additions/Modifications/Conclusion/Rationale Indications and Applicant proposed removal of the Division agreed; efficacy has now been replicated in Usage (1.1) limited use statement for the a second study, the NI margin met the more treatment of cUTI conservative and traditional 10% threshold and the cefiderocol safety database has increased. Indications and Applicant proposed following Division proposed removal of pathogens (b) (6) Usage (1.2) pathogens for the HABP/VABP indication: A. baumannii complex, (b) (6) E. A. baumannii complex retained after coli, E. cloacae complex, discussions with Applicant. Agreement; justification (b) (6) K. for inclusion of A. baumannii complex is noted in pneumoniae, (b) (6) P. section 6.4.3 aeruginosa, S. marcescens (b) (6)

Dosage and Applicant proposed CRRT dosage Division proposed revisions to the effluent flow rate Administration recommendations and Division based dosage in patients receiving CRRT. Division (2.1 and 2.2) proposed revisions. also proposed removal of ESRD from labeling as new terminology has been proposed. Agreement; the in vitro CRRT study and the observed PK data from patients who underwent CRRT in Phase 3 studies supported the effluent flow rate-based CRRT dose regimens (see section 8.1)

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Applicant’s Modification Section Proposed in Labeling Additions/Modifications/Conclusion/Rationale (b) (4) 5. Warnings Division did not accept this change as the and description is relevant to the CREDIBLE-CR trial; A. Precautions baumannii “complex” added for consistency of the (5.1) terminology and to include deaths due to A. nosocomialis.

(b) (4)

(b) (4) 6. Adverse Reactions (6.1)

6. Adverse Applicant proposed the number of Division added ARs leading to death and that the Reactions patients in the FETROJA and most common ARs leading to discontinuation in both (6.1) meropenem groups that had treatment groups were elevated liver tests . serious ARs and ARs leading to Applicant agreed. discontinuation. (b) (4) Division proposed a different incidence rate and additional adverse reactions as follows: anemia, hypokalemia, hypomagnesemia, and atrial fibrillation as selected ARs occurring in ≥4% (Table 5) and occurring in <4%: thrombo-cytopenia, thrombocytosis, bradycardia, myocardial infarction, atrial flutter, intestinal ischemia, abdominal pain, gastritis, chest pain, cholecystitis, cholelithiasis, fungal urinary tract infection, blood creatinine increased, prolonged prothrombin time, PT-INR, aPTT, hypocalcemia, hyponatremia, hyperkalemia, cerebrovascular accident, seizure, dizziness, paresthesia, headache, bronchospasm, stridor, dermatitis. C.difficile infection (b) (4)

Elevations in liver tests and diarrhea were retained in Table 5. Applicant did not agree with any of the additions.

Division agreed to remove anemia, bradycardia, gastritis, chest pain, fungal urinary tract infection, blood creatinine increased, cerebrovascular accident, headache, bronchospasm, stridor, dermatitis (see section 7.6.5 for rationale). Upon further review, blood creatinine increased was changed to acute kidney injury. Applicant agreed with retaining thrombocytosis, myocardial infarction, atrial flutter, abdominal pain, cholecystitis, 180 Integrated Review Template, version date 2019/10/16

Reference ID: 4676324 NDA 209445 / S-002 Cefiderocol (Fetroja)

Applicant’s Modification Section Proposed in Labeling Additions/Modifications/Conclusion/Rationale cholestatis, prolonged prothrombin time, PT-INR, aPTT, hypocalcemia, hyperkalemia and submitted a justification for removing thrombocytopenia, intestinal ischemia, hypomagnesemia, hyponatremia, dizziness, and acute kidney injury. Division agreed to remove intestinal ischemia, hyponatremia, paresthesia, and dizziness but retain the other ARs.

(b) (4)

Appliant proposed to change acute kidney injury to acute interstitial nephritis. Division agreed. 8. Use in Division proposed a description of the differences in Specific safety and efficacy (incidence of ARs, mortality, and Populations clinical cure) based on age group. Applicant agreed. (8.5) 8. Use in Division proposed a adding labeling language on Specific patients receiving CRRT to subsections 8.6 and Populations 12.3. Applicant agreed. (8.6) and 12. Clinical Pharmacology, (12.3)

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Applicant’s Modification Section Proposed in Labeling Additions/Modifications/Conclusion/Rationale 12. Clinical Applicant proposed removal of Division agreed to the removal of mutations of Pharmacology mutations of transcriptional transcriptional regulators that impact expression of (12.4) regulators that impact expression efflux pump and addition of maintenance of in vitro of efflux pump and added activity of cefiderocol against P. aeruginosa in the maintenance of in vitro activity of presence of efflux pump up-regulation (MexAB- (b) (4) cefiderocol against P. aeruginosa OprM, MexCD-OprJ, MexEF-OprN, and MexXY in the presence of efflux pump up- regulation (MexAB-OprM, MexCD- OprJ, MexEF-OprN, and MexXY), (b) (4)

Applicant proposed several Applicant agreed to revisions to the pathogen in the pathogens for the first and first list. A. baumanni complex was retained in the second list. first list based on additional data and further review by the division (see Section 6.4.3). B. cepacia complex, C. koseri, K. aerogenes, K.oxytoca, and S. maltophilia were moved to the second list. (b) (4) was removed from the second list (see section 18). Clinical Applicant proposed tables 11 and Division proposed modification of tables 11 and 12 Studies 12 (ACM and clinical cure by (ACM and clinical cure by pathogen, respectively) (14.1) pathogen, respectively) based on based on susceptibility to meropene (b) (4) susceptibility to both FETROJA and meropenem. and added a comparative analysis of clinical outcomes in all 51 patients with A. baumannii For tables 10 and 11, the complex in both treatment groups. Applicant proposed the following For tables 10 and 11, the division added the pathogens: K.pneumoniae, P. following pathogens to the applicant’s proposal: aeruginosa, Acinetobacter Other Enterobacterales (Includes Enterobacter baumannii complex and cloacae complex (E. cloacae, E. asburiae and E. Escherichia coli kobei) and Serratia marcescens). Applicant agreed.

Abbreviations: ACM, all-cause mortality; aPTT, activated partial thromboplastin time; AR, adverse reaction; CRRT, continuous renal replacement therapy; ESRD, end stage renal disease; MIC, minimum inhibitory concentration; PK, pharmacokinetic; PT, prothrombin time; PT-INR, prothrombin time-international normalized ratio 22. Postmarketing Requirements and Commitments

The following pediatric PMRs were proposed at the time of approval of cefiderocol for the HABP/VABP indication. Conduct an open-label randomized multicenter, active-controlled trial to evaluate the pharmacokinetics, safety and tolerability of Fetroja (cefiderocol) in children from 3 months to less than 18 years of age with cUTI and HABP/VABP. The dose for this study for children 3 182 Integrated Review Template, version date 2019/10/16

Reference ID: 4676324 NDA 209445 / S-002 Cefiderocol (Fetroja) months to less than 18 years of age will be determined by the data from a single-dose, non- comparative study assessing the pharmacokinetics of FETROJA (cefiderocol) in pediatric patients from 3 months to less than 12 years of age with suspected or confirmed gram-negative infections. Final Protocol Submission: 01/2021 Study Completion: 12/2023 Final Report Submission: 04/2024 Conduct an open-label, single arm non-comparative study to evaluate the pharmacokinetics, safety and tolerability of multiple doses of FETROJA (cefiderocol) in children from birth to less than 3 months of age with suspected or confirmed gram-negative infections. The dose for this study will be determined by the data from a single-dose, non-comparative study assessing the pharmacokinetics of FETROJA (cefiderocol) in pediatric patients from birth to less than 3 months of age with suspected or confirmed gram-negative infections. Final Protocol Submission: 06/2022 Study Completion: 08/2024 Final Report Submission: 01/2025 (b) (4)

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Reference ID: 4676324 NDA 209445 / S-002 Cefiderocol (Fetroja) 23. Financial Disclosure

Table 86. Covered Clinical Studies: APEKS-NP Trial Was a list of clinical investigators provided: Yes ☒ No ☐ (Request list from Applicant) Total number of principal investigators identified: 116 Number of investigators who are Sponsor employees (including both full-time and part-time employees): 0 Number of investigators with disclosable financial interests/arrangements (Form FDA 3455): 0 If there are investigators with disclosable financial interests/arrangements, identify the number of investigators with interests/arrangements in each category (as defined in 21 CFR 54.2(a), (b), (c) and (f)): Compensation to the investigator for conducting the study where the value could be influenced by the outcome of the study: 0 Significant payments of other sorts: 0 Proprietary interest in the product tested held by investigator: 0 Significant equity interest held by investigator: 0 Sponsor of covered study: 0 Is an attachment provided with details of the Yes ☒ No ☐ (Request details from disclosable financial interests/arrangements: Applicant) Is a description of the steps taken to minimize Yes ☒ No ☐ (Request information from potential bias provided: Applicant) Number of investigators with certification of due diligence (Form FDA 3454, box 3): 0 Is an attachment provided with the reason: Yes ☒ No ☐ (Request explanation from Applicant)

An attachment to form 3455 was submitted for two subinvestigators for whom a financial (b) (6) disclosure statement could not be obtained. acted as a subinvestigator for the (b) (6) principal investigator (b) (6) acted as a subinvestigator for the principal investigator . During study close out activities, it was discovered that a financial disclosure statement from this subinvestigators could not be found. The study team had reached out to these subinvestigators to obtain a financial disclosure statement post hoc but have been unsuccessful. Therefore, it cannot be confirmed if these subinvestigators had financial interests or arrangements to disclose. In lieu of this confirmation, a form FDA 3455 has been completed, without any boxes checked for both of these subinvestigators. Shionogi confirms that they have not entered into a financial arrangement with these subinvestigators whereby the value of the compensation for conducting the study could be influenced by the outcome of the study. The principal investigators of the sites have also attested that they have entered into no such arrangement. Shionogi also confirms that no payments outside of those related to the APEKS-NP study have been made. This issue is unlikely to alter the results of the trial.

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Reference ID: 4676324 NDA 209445 / S-002 Cefiderocol (Fetroja) 24. References Alp, E, M Güven, O Yildiz, B Aygen, A Voss, and M Doganay, 2004, Incidence, risk factors and mortality of nosocomial pneumonia in intensive care units: a prospective study, Ann Clin Microbiol Antimicrob, 3:17. Chen, Z, P Venkat, D Seyfried, M Chopp, T Yan, and J Chen, 2017, Brain-Heart Interaction: Cardiac Complications After Stroke, Circ Res, 121(4):451-468. Di Bonaventura, G, A Pompilio, R Zappacosta, F Petrucci, E Fiscarelli, C Rossi, and R Piccolomini, 2010, Role of excessive inflammatory response to Stenotrophomonas maltophilia lung infection in DBA/2 mice and implications for cystic fibrosis, Infect Immun, 78(6):2466- 2476. Division of Anti-Infectives, 2019, Multi-Disciplinary Review and Evaluation: NDA 209445, Fetroja (cefiderocol), Food and Drug Administration. Guidance for Industry, Hospital-Acquired Bacterial Pneumonia and Ventilator-Associated Bacterial Pneumonia: Developing Drugs for Treatment (June 2020) Kawai, A, CL McElheny, A Iovleva, EG Kline, N Sluis-Cremer, RK Shields, and Y Doi, 2020, Structural Basis of Reduced Susceptibility to Ceftazidime-Avibactam and Cefiderocol in Enterobacter cloacae Due to AmpC R2 Loop Deletion, Antimicrobial Agents and Chemotherapy, 64(7):e00198-00120. Kelly, J, A Rudd, R Lewis, and BJ Hunt, 2001, Venous thromboembolism after acute stroke, Stroke, 32(1):262-267. MacVane, SH, JL Crandon, WW Nichols, and DP Nicolau, 2014, Unexpected in vivo activity of ceftazidime alone and in combination with avibactam against New Delhi metallo-β-lactamase- producing Enterobacteriaceae in a murine thigh infection model, Antimicrobial agents and chemotherapy, 58(11):7007-7009. Muskett, H, J Shahin, G Eyres, S Harvey, K Rowan, and D Harrison, 2011, Risk factors for invasive fungal disease in critically ill adult patients: a systematic review, Crit Care, 15(6):R287. Pistolesi, V, S Morabito, F Di Mario, G Regolisti, C Cantarelli, and E Fiaccadori, 2019, A Guide to Understanding Antimicrobial Drug Dosing in Critically Ill Patients on Renal Replacement Therapy, Antimicrobial Agents and Chemotherapy, 63(8):e00583-00519. Rouf, R, SM Karaba, J Dao, and NP Cianciotto, 2011, Stenotrophomonas maltophilia strains replicate and persist in the murine lung, but to significantly different degrees, Microbiology (Reading), 157(Pt 7):2133-2142. Schalk, IJ, M Hannauer, and A Braud, 2011, New roles for bacterial siderophores in metal transport and tolerance, Environ Microbiol, 13(11):2844-2854. Shields, RK, A Iovleva, EG Kline, A Kawai, CL McElheny, and Y Doi, 2020, Clinical evolution of AmpC-mediated ceftazidime-avibactam and cefiderocol resistance in Enterobacter cloacae complex following exposure to cefepime, Clin Infect Dis. Spellberg, B and RA Bonomo, 2014, The deadly impact of extreme drug resistance in Acinetobacter baumannii, Critical care medicine, 42(5):1289-1291.

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Reference ID: 4676324 25. Review Team Acknowledgements

Reference ID: 4676324 {See appended electronic signature page}

Reference ID: 4676324 {See Appended Electronic Signature Page}

Reference ID: 4676324 Signature Page 1 of 1 ------This is a representation of an electronic record that was signed electronically. Following this are manifestations of any and all electronic signatures for this electronic record. ------/s/ ------

EDWARD A WEINSTEIN 09/25/2020 02:26:03 PM

SUMATHI NAMBIAR 09/25/2020 05:23:29 PM

Reference ID: 4676324